Keresés

Új remény a szélütés miatt lebénult betegeknek
2005. április 15. 10:34

Egy amerikai csapat olyan fehérjegátló antitesttel dolgozott, mely patkányoknál visszaállította a szélütés következtében lebénult végtagok mozgóképességét

Amikor szélütés ér egy embert, az agy bizonyos területének vérellátása megakad, mivel egy ér károsodik vagy valami elzárja. A vér normál esetben oxigént és tápanyagokat szállít, mely szükséges az agysejtek életben maradásához. A vér nélkül a sejtek haldoklani kezdenek és a szélütés áldozatai elveszítik azon képességeiket, melyeket az adott terület agysejtjei irányítottak. Az összes szélütéses eset 80 százaléka isémiás - elégtelen vérellátás -, melyet vérrögök váltanak ki, amelyek az ereket és az agyi artériákat blokkolják. Ez a trombotikus szélütés. A többi 20 százalék esetén a meggyengült ér elszakad és vérzés indul meg az agyban. Ezt nevezik hemorrágiás szélütésnek, mely gyakran halálos. Évente körülbelül 600 ezer új szélütéses eseteket regisztrálnak.

A megújulás ereje

A fiatal emberek és állatok esetén a központi idegrendszer, mely körülbelül 10 milliárd idegsejtet tartalmaz rendelkezik azon képességgel, hogy spontán módon új idegsejt kapcsolatokat hozzon létre. Így gyakorlatilag nincsen akadálya a regenerálódásnak a fiatal, fejlődő szervezetben. Ám amikor a fiatal állatok felnőnek és idegrendszerük is kifejlődik, ezen spontán reakciók megszűnnek, mert valami blokkolja azokat. A kutatók tudják, hogy a felnőttek ugyanolyan kapacitással rendelkeznek a megújulásra, ám valami van a szervezetben, ami nem engedi a folyamat végremenését.

Az elmúlt években agykutatók nemzetközi csapata Martin Schwab vezetésével felfedezett egy "NOGO-A" néven ismert fehérjét, mely megakadályozza az agy és a gerincvelő sérült idegsejtjeinek gyógyulását és újranövesztését. A protein a jelek szerint az egyik olyan stabilizátor, mely akkor kap szerepet, amikor a központi idegrendszer kifejlődése befejeződött, amikor az összes idegszál helyre került, megvannak a megfelelő kapcsolatok és az egész rendszer funkcionális, érett állapotba kerül.

Wendy Kartje orvos teszteket hajtott végre szélütés utáni állapotban lévő patkányokon egy speciális antitest segítségével. Ez az antitest egy immunrendszer fehérje, mely meggátolja, hogy a NOGO-A megkösse az idegsejteken lévő receptorokat. A NOGO-A gátló hatása nélkül a sérült idegsejtek képesek voltak regenerálódni, így az állatok lebénult első végtagjukban visszakapták a mozgás képességét. A kutatók most először bizakodóak azzal kapcsolatban, hogy a szélütéses embereken így segíteni tudnak.

Az orvoscsapat előzőleg arra tanította be a patkányokat, hogy komoly feladatokat hajtsanak végre, például egy apró lyukon keresztül másszanak az ételig, vagy egy kis létra fokain menjenek fel. Ezen feladatok nagy része precíz elülső végtagmozgást és koordinációt követelt. A szélütésszerű sérülés a motoros kéregállomány bal vagy jobb részén - az agy azon része, mely a tudatos mozgásokat irányítja - azt eredményezte, hogy az állatok azonos oldalon lévő végtagjai lebénultak, így nem tudták végrehajtani a feladatokat.

Egy héttel a szélütés után megkezdték a patkányok kéthetes antitest-kezelését, hogy blokkolják a NOGO-A fehérjét. A kezelés végén a kutatók állandó teszteket kezdtek meg az állatokkal. Öt héttel a bénulás után, a kezelés hatására drámaian változott a rágcsálók állapota. Amikor a kutatók megvizsgálták az agyi kapcsolatokat, kiderült, hogy újak jöttek létre a hiba áthidalására. Bár Kartje csapata csak az agy azon részén tesztelte a terápiát, mely a mozgást irányította - a szélütés során leggyakrabban károsodó terület - , a csapat szerint más jellegű szélütés esetén is alkalmazni lehet a fehérje gátló kezelést.

A kérdés már csak az, hogy mennyi idővel a szélütés után kell bevetni a terápiát, hogy az működjön. A csapat most ennek meghatározásán dolgozik. A kutatók szerint, ha a terápia hasznos - rágcsálóknál egy hónap után az volt - akkor embereknél hosszabb idő után is be lehet vetni, és nagy valószínűséggel hatni is fog.

Rokonszenves bubo kitartása.

A Huang cikkhez: Vannak tudományos dolgok, van szakmai irigység, van maradi szemlélet és van tévhit. Dr. Huang módszere új, forradalmi, és noha bizonyos eredményei hagynak kétséget maguk után, ami tény , az az, hogy kárt még nem okozott és tény az is, hogy sok páciensénél funkcionális javulás volt elérhető. Az új módszerek, néha rizikós alkalmazása viszi előre a tudományt. Az, hogy ezt sok helyen korlátozzák részben indokkal, részben túlzott félelemtől vezérelve, részben maradi szemlélet, vagy pedig szakmai irigység miatt. az más kérdés.

Orvostudomány Csontvelő-őssejtekből idegsejtek 2005. március 23. 08:18 Norvég kutatók emberi csontvelő-őssejtekből idegsejteket állítottak elő Az Oslói Egyetem kutatói felnőtt emberi csontvelőből kivont őssejteket sikeresen idegsejtekké alakítottak úgy, hogy sérült csirkeembriókba ültették azokat. A tudományos áttörés teljesen újfajta sejtforrásokhoz vezethet, melyeket a Parkinson kórhoz hasonlatos betegségek gyógyításánál alkalmazhatnak. A jelek szerint az embriók belső gyógyító mechanizmusa úgy hatott a sejtekre, hogy azok megváltoztassák funkciójukat. Az őssejtek olyan sejtek, melyeknek megvan azon képessége, hogy különböző szövetekké képesek alakulni. Ám azok, melyeket felnőtt csontvelőből vonnak ki általában vér és immunsejteket termelnek. Ugyanakkor a kísérletek azt sugallják, lehetséges idegekké alakítani ezeket a sejteket. Az ilyen jellegű kísérletek a múltban sikertelenek voltak. Néhány esetben a kutatóknak sikerült azonosítani a neuronok molekuláris jelzéseit, ám ezek aztán sosem voltak képesek megfelelően egymáshoz csatlakozott sejtekké válni. Ugyanakkor a csontvelő-őssejtjeit csirkeembriókba ültetve tökéletesen funkcionáló sejteket sikerült létrehozni. A kutatók szerint ezzel a kísérlettel teljesen új lehetőségek nyílnak az idegsejtek előállításában emberi csontvelőből. A norvég csapat mikrosebészeti technikát alkalmazott, hogy a növekvő embrió fejlődő gerincvelejéből kicsippentsen egy apró darabot. A csontvelőből származó emberi vérképző őssejteket (hHSC) aztán beültették a sérült területre. A tojásokat aztán az embriók eltávolítása előtt inkubációba helyezték, majd kimetszették az emberi sejteket tartalmazó gerincrészt és elemezték azt. A fejlődő agy és gerincvelő károsodásai a csirkeembriókban az úgynevezett regulatív regeneráció során automatikusan meggyógyultak. Ezen gyógyító folyamat jelei kulcsfontosságú információkat szolgáltattak az őssejteknek, így azok bekapcsoltak és idegsejtekké alakultak. A 154 embrió 60 százalékánál jelentkezett a regenerációs folyamat és a csontvelő őssejtek beépültek a fejlődős gerincvelőbe. A kísérletek során nem tapasztalták az emberi sejtek kilökődésének veszélyét, vagy gyulladásos reakciókat. Az elemzések azt mutatták, hogy az őssejtek kapcsolatba léptek gazdasejtjeikkel, hogy egyfajta hibrid, ember-csirke sejtet hozzanak létre, mely megelőzi bármely kezelés szükségességét. A kutatók azt remélik, lehetővé válik idegsejtek növesztése laborkörülmények között is úgy, hogy imitálják a csirkeembriókban található sejtjelzéseket

Mert a magyar piac nem eleg nagy egy technikai ujsag eltartasahoz :-(.

Miért nem magyarul vannak az ilyenek...

Bocs, kicsit hosszu lesz, de nagyon tanulsagos:


TechnologyReview.com
The Problematical Dr. Huang Hongyun
By Horace Freeland Judson Jannuary 2005

Anesthetize the rat. Lay it belly down. Shave a patch along its spine and cut to the bone. Do a laminectomy, that is, take the bone off a short length of the back of the spine, exposing the spinal cord. Suspend a 10-gram rod above the spinal cord, at a height of 12.5 millimeters, or 25, or 50 millimeters. Let it drop.

The result will be a bruise, or more technically, a contusion, of the rat’s spi­nal cord. The bruise interrupts nerve transmission, paralyzing some muscles and blocking sensation. The location and severity of the damage will depend on the site of the blow and the height of the drop—and the consequent behavioral changes are reproducible. The procedure was developed in the early 1990s in the laboratory of Wise Young, a neurologist then working at New York University and now at Rutgers. He wanted to create a model for spinal-cord injury, in order to test and evaluate proposed treatments to repair the damage and restore some degree of function. Not long before, three scientists at Ohio State University had devised a rating scale for precise scoring of loss of function in spinal-cord injury. Young adapted the scale to his rat model, based on how well or poorly an injured creature could walk. In 1995, he showed that the behavioral rating varies in direct proportion with tissue damage at the injury site. In a recent conversation, he said, “This was the first behavioral outcome measure that correlated with morphologi­cal damage in the spinal cord.” Although no one measure is universally accepted ­in spinal-cord-injury work, Young said, “This comes close.”

The spinal cord is remarkably well protected, by bone and by its tough outer layer, the dura. In humans, only about 10 percent of spinal-cord injuries, caused by mishaps like a bullet through the spine, interrupt the cord completely. Ninety percent are contusions. Nerves in the adult central nervous system, including the spinal cord, do not spontaneously regenerate. Some nerves in the peripheral system, however, can—importantly, in the presence of Schwann cells, a type of cell that provides an environment favorable to new growth of nerve axons. Many attempts have been made to transplant such cells into damaged spinal cords, to promote regeneration, but they have all failed.

Enter olfactory ensheathing glial cells—bearing the hope of a way to fix, or at least to ameliorate, spinal-cord injuries. In 1984, Ron Doucette, at the University of Saskatchewan, described a new kind of cell, which he had found in the olfactory nerve and the olfactory bulb. The olfactory nerve is the only central-nervous-system nerve that continually regenerates throughout adult life. It is made up of neurons that arise in the mucous tissue of the nose and run the short distance to the olfactory bulb, one of the most primitive parts of the brain.

We sniff substances all the time that are toxic to these neurons, which die and must be replaced. New ones are constantly being generated. They send axons up the olfactory nerve to establish fresh connections to the bulb. Doucette’s new-found cell produces a particular protein that marks it as a glial cell—a class of support cells, which include Schwann cells, that surround neurons. The surface of Doucette’s cell carries what are called cell-adhesion molecules, which attract growing axons. In the years after his discovery, Doucette isolated these cells and learned to grow them in tissue culture. He found that they wrap around axons and promote their growth: hence the name, olfactory ensheathing glial cells. In 1990, Doucette proposed that they are the principal reason the olfactory nerve can regenerate. Then and today, he has been pursuing how exactly Schwann cells and ensheathing cells do what they do.

The exciting question was whether the glial cells might encourage regrowth of spinal-cord neurons. Several scientists jumped on it, conspicuously Almudena Ramón-Cueto of the Universidad Autó­noma de Madrid in Spain and Geoffrey Raisman at the National Institute of Medical Research in London .

Ramón-Cueto first tried cutting the peripheral nerves of rats at the point, called the spinal root, where they connect with the spinal cord. Such injuries are crippling. Normally the nerves will not grow back into the spinal cord. She then transplanted some of the creatures’ own olfactory ensheathing glial cells into the region of the root, and in 1994, she claimed that this allowed the nerves to regenerate their connections. She then went to work with Mary Bunge of the Miami Project to Cure Paralysis, which is at the University of Miami. Bunge’s main approach has been to graft Schwann cells into rats’ spinal cords, bridging spinal lesions, and then to try various measures, including drugs in different combinations, to get them to grow. In 1998, she and Ramón-Cueto injected adult-rat olfactory ensheathing glial cells into the areas at each end of the Schwann bridges. They reported that six weeks after the combined graftings, spinal-cord axons were growing through the Schwann cell bridges and beyond—and that the ­ensheathing cells had migrated, accompa­nying growing axons through and along­side the Schwann bridges.

Raisman, meanwhile, was also experimenting with olfactory ensheathing glial cells. In 1985, he had suggested that these cells had special properties that enabled them to repair central-nervous-system neurons. Now, in a clever experiment, he used a thin electrode to burn through rat spinal cords on one side only, at a point that left the creatures able to use only one forepaw. Before the operation, he had trained the rats to reach through a hole for pellets of food with their forepaws, using one or the other with equal facility; afterwards, they were unable to reach with the affected limb but could use the other normally. He then transplanted into the spinal lesions a mixture of cell types, including olfactory ensheathing glial cells. In 1997, Raisman and colleagues reported in Science that as early as ten days after the transplants, spinal-cord axons sprouted and grew across the lesions. Two to three months after the transplants, of a group of seven rats, four were able to use either forepaw as adeptly as normal rats. Dissection showed that these four had regrown spinal-cord axons across the lesions.

In 2000, after returning to Spain, Ramón-Cueto published a paper in the journal Neuron asserting that when she transected the spinal cords of rats and injected olfactory ensheathing glial cells into the lesions, many of the rats recovered some locomotor function. The degree of regeneration and recovery was slight, and some raised questions about exactly how she did the tests. Yet the paper had impact.

The pressure is now intense to get to clinical trials. The United States alone has on the order of 200,000 patients with spinal-cord injuries. (Their plight was dramatized by Christopher Reeve, the quadriplegic Superman and spinal-cord campaigner, who died on October 10, 2004.) Raisman is pushing toward trials, as is Ramón-Cueto. In June 2003, Raisman told the BBC, “My guess is we are probably two to three years away. It could be less.” A group in Brisbane, Australia, led by Alan Mackay-Sim, has duplicated the rat experiments with ensheathing cells and is at the stage of exploratory clini­cal trials; Carlos Lima, from the Egaz Moniz Hospital in Lisbon, has treated a small number of patients. Yet extreme caution is obviously necessary: the procedure raises great scientific, medical, regulatory, and ethical problems. In a recent telephone conversation, Doucette emphasized repeatedly that the basic physiology is still not understood. “Just putting the cells in and saying, ‘Oh, great, we’ve got some functional recovery,’ and then moving on to the next step, to me isn’t satisfactory. I want to know how it happened. Why. And how you can control it,” he said. He went on: “My view is that I think we’re probably five, ten years away. In terms of being at a stage where I’m confident we know enough about what’s going on.”

Enter Dr. Huang Hongyun.

The Paper
In 1999, a Chinese neurosurgeon named Huang Hongyun arrived at New York University School of Medicine from Beijing, wanting to work with Wise Young and learn about spinal-cord injury. Young had moved to Rutgers, so Huang followed him there. “He wanted to know what to do,” Young said. “Studies recently published had claimed that olfactory ensheathing glial cells transplanted into spinal cords would regenerate rats and improve locomotor recovery. I was skeptical about some of the results. They were mostly based on, I thought, fairly questionable behavioral outcome measures. So I suggested to him, Why don’t we do it in our spinal-cord injury model?” Huang worked with Young for several years, then moved back to Beijing, becoming chair of neurosurgery at Chaoyang Hospital.

Almost at once, Huang began operating on human patients with injured spinal cords. In March 2003, he and colleagues submitted a four-page paper to the Chinese Medical Journal, which published it in October of the same year.

The journal is something of a historical oddity. It comes out monthly, about 100 pages an issue, entirely in English except for contributors’ names. It was founded in 1887 by missionaries who wanted to bring Western medical methods and standards to China and needed an English-language publication that would present the best of modern Chinese medi­cal research and clinical practice. In the first half of the 20th century, it was well respected; after the Communist takeover of mainland China, it declined badly. Only in the last five years or so has the journal begun to regain quality and the respect of non-Chinese scientists. But scientists do not consider the journal to be peer reviewed—at least, not to Western standards. Submitted manuscripts may be looked over by various senior medical-­faculty members, but if anything, this is a liability, for a uniquely Chinese reason: Confucian tradition still inculcates profound respect for elders. To turn down a paper submitted by a senior person would be an act of disrespect.

Huang’s paper reported results of surgery on 171 patients, 139 male and 32 female, ranging in age from 2 to 64 years, with the average age just under 35. All had suffered extensive paralysis and loss of sensation. The time since injury was at least six months and as much as 18 years. All had received previous therapy of one sort or another, for example, administration of nerve-growth factors and surgery, if that had been necessary to relieve pressure on the spinal cord. A requirement was that magnetic-resonance imaging showed no gap in the spinal cord and no compression.

The surgical procedure, which the paper described in detail, is essentially to perform a laminectomy at the site of the damage, open the dura, and inject ensheathing cells. These Huang derived from olfactory bulbs. Although the paper does not mention this, in later discussions Huang has said that the cells come from fetuses aborted in the fourth month of pregnancy. (But they are not stem cells, as has sometimes been reported.) He grows them for two weeks in cell culture, as he learned to do in Young’s lab. He then injects 50 microliters of a cell suspension, approximately half a million cells, into the spinal cord, next to the ends of the lesion.

Before the operation, patients were assessed for degree of paralysis and for sensitivity to light touch and to pinpricks, following an international standard. They were reassessed between two and eight weeks later. The paper claimed that patients made significant if relatively slight improvement in these measures. However, the data are scanty and impossible to evaluate reliably. The subjects are grouped by age but not differentiated further, not even, say, into male and female. The paper describes no individual cases. It offers no before and after scores, just degrees of improvement, and these as averages within each age group. It says nothing about possible deleterious effects, not even that there were none. It reports no long-term outcomes.

Huang has published nothing more.

Sound and Fury
The report drew immediate and intense attention. Discussion groups sprang up on the Internet; within weeks, thousands of patients from the United States and elsewhere had got in touch with Huang. First to report the story in print was Jerome Groopman, at the New Yorker, in a profile of Christopher Reeve published on November 10, 2003; he described a range of animal experiments that Reeve was following, including Young’s and especially Ramón-Cueto’s, and gave five paragraphs to the promise of Huang’s work and some of its problems.

In February 2004, in Vancouver, British Columbia, a consortium called the International Campaign for Cures of Spinal Cord Injury Paralysis held a two-day international workshop on clinical trials. Several speakers presented preliminary results of treatments involving drugs. Three spoke of clinical trials involving olfactory ensheathing glial cells, surgically implanted. Mackay-Sim, from Brisbane, described an initial human trial testing the safety of his procedure. He used ensheathing cells from each patient’s own mucosa, purified and grown for six weeks in culture, then injected at 40 small sites in and around the patient’s spinal lesions. Four patients got transplants; four got placebos. His assessments before and afterwards were elaborate and blind, the best in the business so far. Results were not yet in. Lima, from Lisbon, reported that he had treated seven patients by taking portions of their own olfactory mucosae, containing many sorts of cells, and transplanting these directly into spinal-cord lesions. Improvements were minimal, and one patient got worse. Lima used no placebos, and assessments were not blinded.

Huang reported his work—announcing that he had now given fetal-olfactory-­ensheathing-cell transplants to more than 300 patients, including a number of Ameri­cans and other Westerners. Some patients, Huang said, showed improvements two or three days after the operation, although all experimental evidence said that nerves could not regrow that fast. He had tried no placebos; his assessments were unblinded and were thought rudimentary. He reported no adverse consequences, although with so many cases that was implausible. Follow-up was minimal and never conducted more than a few months after the procedure. The ethical risks were obvious and considerable.

James Guest and Eva Widerstrom-Noga, both physicians working with the Miami Project to Cure Paralysis, attended the Vancouver meeting. They came home with grave reservations; nonetheless, Bunge and her colleagues decided they needed to know more. They invited Huang to come to Miami.

Media attention built. On April 13, the Detroit Free Press ran a story about the Rehabilitation Institute of Michigan, located on the campus of the Detroit Medical Center. The previous fall, the institute had announced it would screen patients for possible operations in China or Portugal. After that, two patients had gone abroad, Robert Smith to Beijing and Erica Nader to Lisbon. While in the United States, Huang had visited the Rehabilitation Institute. Now with a waiting list approaching a hundred, the institute said that in August it would open an outpatient center where applicants would be evaluated and patients returning from China or Portugal would be monitored. The institute was already following up with Smith and Nader, and the newspaper’s account of their progress, though cushioned with language like “steady progress” and “long road to recovery,” was glowing.

That same day, public broadcasting stations aired an hour-long program called “Miracle Cell,” part of the starry-eyed series Innovation. Though it didn’t mention Huang, the program presented Lima’s work in Lisbon, enthusiastically overstating the progress his patients had made, and gave Raisman in London a platform from which to announce his plans for clini­cal trials. “Miracle Cell” repeatedly confused fetal olfactory ensheathing glial cells with stem cells.

Huang lectured at the Miami Project on May 5, 2004. Guest arranged to visit him for 10 days in July, accompanied by Tie Qian, a physician specializing in physi­cal medicine and rehabilitation with the Miami Veterans Affairs Medical Center who is Chinese and speaks the language.

The second week in June, Tim Johnson, a reporter for the Knight Ridder News Service, filed an article from Beijing about Huang, his hospital, and his claims. It was picked up by a number of papers in the chain, including the Lexington, KY, Herald-Leader and the Miami Herald. On July 30, the Scientist, a weekly magazine of science news and features, carried an article about Huang. The Asian edition of Time ran a similar story from Beijing in its August 16 issue.

On August 27, the Chicago Tribune ran an article by Michael Lev that began, “A Chinese neurosurgeon has been besieged by desperate Americans willing to pay $25,000 for an implant of cells from aborted fetuses, a controversial and scientifically unproven procedure.” The piece was more thorough than most in voicing the uncertainties and reservations about Huang’s claims. Yet febrile publicity and desperate hope were by that time driving the public response. In Lev’s article Huang claimed that he had performed 450 transplants, while the waiting list for his procedure had grown to more than a thousand, including a hundred Americans.

A House Call
At half past eight on the morning of Friday, September 10, 2004, a meeting began at the laboratories of Massachusetts General Hospital. Huang was to speak. The meeting was limited to physicians and scientists. The chief organizer was Robert H. Brown, a professor of neurology at Harvard Medical School and director of the Day Laboratory of Neuromuscular Research at Mass. General. I had spoken with him by telephone early in the week; he told me he was skeptical.

Huang is of medium height, with a receding chin, and seemed somewhat diffident. His English is limited and strongly accented. He was there, it turned out, not to present his work on spinal-cord injury but to discuss another project that, he said, he had begun 18 months earlier. The title of his talk was “Olfactory Ensheathing Cell Transplantation for Amyotrophic Lateral Sclerosis.” ALS is the devastating nerve disorder better known as Lou Gehrig’s disease. (The accounts in the Scientist, Time Asia, and the Chicago Tribune had mentioned Huang’s turn to ALS.) Huang offered some minimal PowerPoint slides. His summary claim, at beginning and end: “OEC transplantation is safe, feasible, and rapidly improves partial func­tion. Results are observable in two or three days, and improvement continues for two to three months. The mechanism is unclear.” However, his data were shockingly thin—indeed, insultingly so, I came to think. He finished up with half a dozen brief, blurry before-and-after videos of six of what he said had been a set of eight ALS patients, newly able to walk, or to stand, or to sit up, or to move the tongue enough to talk, if indistinctly. Each was followed by charts depicting nerve function before and after the transplant surgery.

His audience treated him with caution and courtesy, while its skepticism and impatience steadily increased. Much of the simplest factual information—pre-data, one might call it—was missing. Halfway through the question period, I asked several questions. When did his work with ALS patients begin? January 2003, he answered. But the videos carried dates, and these were as recent as mid-August 2004, just three weeks earlier. How many patients had he treated? He gave no clear answer; after follow-up questions from others, the likely number seemed to be 10 or 11—until he said there had been “about 40.” Did they all get fetal cells? No answer.

As the questioning went on, problems with Huang’s methodology seemed to emerge, chiefly the lack of rigorous pre- and postoperative evaluation of patients’ functioning, the lack of controls, and, above all, the total absence of follow-up beyond a few months.

On his home ground, Huang is more assured, smoother. Indeed, with Chinese visitors and with patients, he evinces a certain quiet charisma. Chaoyang Hospital, Beijing, is part of a set of gray, grimy stone buildings around a gated courtyard, with no clear indication of which is its main entrance. Huang’s office is on the hospital’s top floor, but we met on the second, in a serviceable workroom with a central set of tables and, around the walls, shelves haphazardly filled with equipment and supplies. The room sits at the head of a dim corridor along which open, on either side, wards with six beds each, some empty, some occupied by patients, though not all are spinal-cord cases. The patients are surrounded by members of their families—as is customary in China, where much of patients’ care falls to relatives.

Huang and I discussed his procedures in detail. Some who had heard him in the United States wondered whether the cells he implanted were a raw mixture or purified. “We get the olfactory bulb out,” Huang said. “Of course, mixture. Then we culture them and purify them.” The dose for a spinal-cord patient is one million cells, “90 percent OEG cells.” Had he published anything about safety? He ducked the question at first, then said that the cells caused “no long-term fever.” He elaborated: “No problems with the cells; maybe we have complications of the surgery—infection of the area, leakage of the cerebrospinal fluid. The general complications of other surgery.”

How much did patients gain? Again, he ducked. Before and after the procedure, he said, patients were evaluated by three doctors, according to standard protocols, for movement, for control of the anal sphincter, and for sensitivity to touch and pinprick. Did any patients have adverse reactions? “Ah, a very complicated question.” But then, “In actual score, no patient got worse.” But the degree of improvement? These patients are in bad shape, he said. “Any improvement is a bonus.” Any complete cures? “I don’t think it is pos­sible to cure this disease.” Even when progress is minimal and gradual, Huang said, it is valuable. “Complete chronic injury, no chance to get 100 percent.”

Critics in the United States have suggested that any patient with spinal-cord injury or, for that matter, ALS who comes to a medical center for some major procedure will probably get a variety of other treatments at the time, and this by itself might provoke temporary improvement. Did patients at Chaoyang Hospital get other treatment as well—such as physical therapy or other rehabilitative help? “No,” Huang said. Physical therapy is not routine in China. “They go home.”

What about follow-up? “They start to improve in two or three days. Then we follow them in two to four weeks. Then another follow-up three to six months.” But what about the longer term? Again, critics have held that patients ought to be tracked for at least two years. Huang hesitated. Then, “Chinese patients very poor. They go home.” He said he could not get in touch with them again.

Had Huang tried to publish other papers, and in peer-reviewed Western journals? Several, he said, but so far no response. He was collaborating on a paper with Guest and Qian from the Miami Project. During their visit to China, Huang said, “They evaluated one patient” before and after surgery. “Totally paralyzed. After surgery, can do this, can do this”—he was making small finger and hand motions. How quick was the recovery? “Second day after, Dr. Guest and Dr. Qian saw some difference.” What could possibly be the mechanism for change that soon? “In front of all eyes, we saw some change, even though they know we couldn’t explain it.” In mid­-October, Guest sent the completed case report to Huang, but a month later Huang still had not found time to look at it.

Huang told me that hospital policy prohibited my watching the surgery. Guest and Qian during their visit examined 12 spinal-injury patients. They formally assessed six of them before and after and indeed observed four operations. They acknowledge that some of the patients demonstrated a degree of modest improvement in motor and sensory function—and that the improvement occurred surprisingly soon. However, two patients showed “wound breakdown,” one of them suffering “a reduction in leg function.” A third patient came down with meningitis. “The Chinese clinicians did not record these complications in the medical record,” asserts an unpublished report by the Miami Project. Although Guest and Qian did watch surgery and observe patients, they were not allowed into the labo­ratory where the cells for transplantation were prepared and had no way to know the content of the putative human fetal ­olfactory-bulb cultures—not even whether the material transplanted actually contained ensheathing cells. Guest adds, “We did see one set of cultures that showed robust cell growth and morphology that could be ensheathing glia. They were very healthy cultures. We viewed them in Dr. Huang’s clinical office.” The chief problem they saw, however, was the lack of long-term follow-up, including full records of any adverse effects.

To me, the most disturbing sign was Huang’s evasiveness. He pleaded repeatedly that patients needed to be treated: “These are suffering, dying people. I am a surgeon. The first thing is to save lives and alleviate suffering.” Though this sentiment may be genuine in Huang’s case, such evasions are a classic mark of the charlatan. Alternatively, he asserted that important types of controls (for example, surgery that mimicked the operation but injected not cells but salt water) would be dangerous and unethical. He insisted repeatedly that the procedure is safe.

Huang’s methodology is a moving target: from work with spinal-cord lesions to ALS, from injections into the spinal cord to injections into brain tissue. Critics have demanded that the procedure involve a fixed quantity of injected cells, one or a few standard points of injection, and significant blinded controls, and that evaluation follow a standardized protocol, including, for example, rigorous pre- and postoperative physiological tests that measure such properties as breathing, muscle tone, and strength.

Deadly Decisions
Despite the defects in Huang’s work, no definitive judgment is yet possible. Wise Young is a cautious advocate. He notes, “There are really no randomized clinical trials for any of the current neurosurgical procedures.” Regarding Huang’s work, “The big debate right now is, What is the level of evidence that’s necessary and sufficient to take something to clinical trial?” Meanwhile, though, when dealing with spinal-­cord patients and their families, “My official recommendation is that they should wait. Many of them ignore me; they go on ahead to do it anyway.” Mary Bunge and her colleagues at the Miami Project find Huang’s claims frustrating. “Presently, Dr. Huang’s project by research standards in the United States is not a clinical trial but is a clinical treatment series. The treatment series does not meet the design standards for a clinical trial that would allow for definitive results to be obtained.” Yet they call for “independent and impartial assessment of the risks and benefits of this cell therapy.” Meanwhile, though, “Miami Proj­ect faculty do not endorse this pro­cedure and at this time would not advise individuals to undergo this surgical transplantation strategy. While some people with SCI will view these current experimental procedures abroad as their only hope, by participating they may be putting themselves in harm’s way.”

The science of Dr. Huang Hongyun raises to our awareness this deep tension over standards of evidence and the ethics of clinical practice.

I saw Huang the afternoon of October 20, 2004. A correspondent from the Mobile, AL, Register, Karen Tolkkinen, was also in Beijing, Huang said; he was to treat several Americans with ALS that week, and one was from Alabama. That evening, he operated on Ronnie Abdinoor, a 47-year-old from New Hampshire. On October 29, Tolkkinen reported in the Register that Abdinoor had died.

http://www.eurekalert.org/pub_releases/2005-01/uow-wsg012605.php MADISON - After years of trial and error, scientists have coaxed human embryonic stem cells to become spinal motor neurons, critical nervous system pathways that relay messages from the brain to the rest of the body. The new findings, reported online today (Jan. 30, 2005) in the journal Nature Biotechnology by scientists from the University of Wisconsin-Madison, are important because they provide critical guideposts for scientists trying to repair damaged or diseased nervous systems. Motor neurons transmit messages from the brain and spinal cord, dictating almost every movement in the body from the wiggling of a toe to the rolling of an eyeball. The new development could one day help victims of spinal-cord injuries, or pave the way for novel treatments of degenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. With healthy cells grown in the lab, scientists could, in theory, replace dying motor neurons to restore function and alleviate the symptoms of disease or injury. Much sooner in the future, the advance will allow researchers to create motor neuron modeling systems to screen new drugs, says study leader Su-Chun Zhang, an assistant professor of anatomy and neurology in the Stem Cell Research Program at the Waisman Center at UW-Madison. Scientists have long believed in the therapeutic promise of embryonic stem cells with their ability to replicate indefinitely and develop into any of the 220 different types of cells and tissues in the body. But researchers have struggled to convert blank-slate embryonic stem cells into motor neurons, says Zhang. The goal proved elusive even in simpler vertebrates such as mice, whose embryonic stem cells have been available to scientists for decades. One reason scientists have had difficulty making motor neurons, Zhang believes, may be that they are one of the earliest neural structures to emerge in a developing embryo. With the ticking clock of development in mind, Zhang and his team deduced that there is only a thin sliver of time - roughly the third and fourth week of human development - in which stem cells could be successfully prodded to transform themselves into spinal motor neurons. In addition to the narrow time frame, it was also critical to expose the growing stem cells to an array of complex chemical cocktails. The cocktails constitute naturally secreted chemicals - a mix of growth factors and hormones - that provide the exact growing conditions needed to steer the cells down the correct developmental pathway. "You need to teach the [embryonic stem cells] to change step by step, where each step has different conditions and a strict window of time," says Zhang. "Otherwise, it just won't work." To differentiate into a functional spinal motor neuron, the stem cells advanced through a series of mini-stages, each requiring a unique growing medium and precise timing. To start, the Wisconsin team generated neural stem cells from the embryonic stem cells. They then transformed the neural cells into progenitor cells of motor neurons, which in turn developed in a lab dish into spinal motor neuron cells. The newly generated motor neurons, according to Zhang, exhibit telltale electrical activity, a sign that the neurons, which normally transmit electrical impulses, were functional. The spinal motor neuron cells have survived in culture in the lab for more than three months, says Xuejun Li, an assistant scientist in Zhang's group, and the lead author of the study. To determine the exact recipe for motor neuron growth, Li foraged labs worldwide to obtain the growth factors and other natural chemicals needed to guide cells from one stage of motor neuron development to another. But once past a certain point, Li found that the cells kept veering off toward different cellular destinies. After hundreds of unsuccessful variations of growth factors and morphogens, Li was struck by an idea: Why not apply a chemical known to be necessary for a later stage of neuron development to a much earlier step in the process? The hunch paid off and turned out to be the final piece of the puzzle. The discovery, says Zhang, demonstrates that human stem cells do not necessarily differentiate in linear fashion, as scientists always believed. Rather, a series of complex overlapping changes may well be the developmental norm in higher vertebrates such as humans. "We cannot simply translate studies from animal to humans," says Zhang. The next step, Li says, will be to test if the newly generated neurons can communicate with other cells when transplanted into a living animal. The team will first test the neurons in chicken embryos. While the new results are promising and provide access to critical cells that may one day be used in therapy, it will likely be many years before they can be tested in humans, Zhang says.

Csodás gyógyulás őssejtekkel MTI 2004. november 19., péntek 18:00 Agyvérzés következtében féloldalára megbénult és meg is némult egy 54 éves brazíliai asszony, de miután agyába beültették saját őssejtjeit, újra járni és beszélni tudott - jelentették be Rio de Janeiróban, ahol először próbálkoztak meg ezzel a gyógyító eljárással. Dr. Hans Fernando Dohman, a brazil nagyváros szívkórházának igazgatója óva intett attól, hogy a világon egyedülálló esetből általános következtetéseket vonjanak le, de annak a véleményének adott hangot, hogy az legalább "a kezelés kutatásában" új fejezetet nyitott. A jövőben 14 másik személyen próbálkoznak ilyen kezeléssel. Az őssejteket a beteg medencéjének csontvelejéből nyerték, és öt nappal az agyvérzés után injekciózták be a páciens agyába egy katéter segítségével. A katétert a nő egyik combi artériáján keresztül vezették be, az őssejteket azonban csak az agyi középső artériában bocsátották szabadon, ott, ahol általában bekövetkezik az agyvérzés. Az őssejtek 17 nap alatt képesnek bizonyultak új vérerek kialakítására, ily módon javult az agy szóban forgó részének vér-, oxigén és glukózellátása, és ez hozzájárult az idegsejtek regenerálásához. A gyógyulóban lévő Maria da Graca Pomeceno asszonyt bemutatták a televízióban, amint felmegy háza lépcsőjén és néhány szót is mond - holott közvetlenül az agyvérzés után nem tudott lábra állni és meg sem tudott szólalni.

In a world first, Australian researchers have discovered a mechanism for greatly enhancing regrowth of spinal cord nerves after they are damaged, restoring the ability to walk in mice within weeks of a spinal cord injury. The University of Melbourne research team, led by Dr Ann Turnley at the Centre for Neuroscience and Professor Mary Galea at the School of Physiotherapy, found that removal of a molecule called EphA4 resulted in significant regrowth of the spinal nerves following injury. Mice without EphA4 regained 100% of their initial stride length within three weeks of the injury and by one month had regained ankle and toe movement. Their ability to bear weight on the affected limbs, to walk and climb also improved and continued to do so for at least three months after the injury. Anatomical analysis revealed that a large percentage of the spinal cord nerves had managed to grow across the damaged area of the spinal cord. Dr Turnley says “when a person injures their spinal cord the effects are often devastating and there is usually little chance that they will regain much movement. There is an enormous amount of research being done around the world to enhance recovery of people with spinal injuries. “In the past it was believed that adult nerves lacked the ability to regrow but work over the last few years has shown that not to be true and we are now beginning to understand the mechanisms behind regrowth and how to enhance it. Our recent findings are a major step forward in this regard.” Dr Turnley says that EphA4 has been known for some time to be involved in guiding nerves during development but their role in the adult was unknown. “The body enhances production of EphA4 following spinal cord injury and we thought it therefore could prove pivotal in determining the outcome of injury in the adult central nervous system. “The surprising result we found was that EphA4 plays a vital role in activating cells called astrocytes which are in turn responsible for forming scarring in the damaged spinal cord, leading to inhibition of nerve regrowth. Mice without EphA4 have very little scarring in the spinal cord and so the nerves can regrow.” Findings of the study, which will be published in The Journal of Neuroscience on November 10, are the work of PhD student Ms Yona Goldshmit, at the University of Melbourne’s Centre for Neuroscience and School of Physiotherapy, in collaboration with Professor Perry Bartlett, Director of the Queensland Brain Institute at the University of Queensland and formerly at the Walter and Eliza Hall Institute of Medical Research. Professor Galea says “this finding provides an exciting possibility for overcoming spinal cord injuries and promoting nerve growth. Increased EphA4 expression has already been observed in primates following spinal cord injury and most likely plays a similar role in humans. “There is now a real prospect of effectively promoting the regrowth of damaged spinal cord nerves after injury in humans by developing drugs that can block the EphA4 molecule and stop the scar from forming in the first place.” http://uninews.unimelb.edu.au/articleid_1908.html

A piece of the puzzle of how nerves find their way across the midline of the brain and spinal cord in a developing embryo has been found by Medical College of Georgia researchers. They have found that an enzyme called focal adhesion kinase tells the arm-like extension of a neuron to cross the midline of the spinal cord, says Dr. Wen-Cheng Xiong, developmental neurobiologist and lead author on the paper in the November issue of Nature Neuroscience. After crossing, the axon becomes part of the complex network that enables the right side of the brain to control the left side of the body and vice versa. The finding helps explain normal development of the nervous systems and provides a new target in the search for ways to re-establish connections -- and the movement and feeling they enable -- lost to spinal cord injuries. “This kinase plays a role in helping direct axon movement across the spinal cord during development,” Dr. Xiong says. “How it does that is one of the questions we hope to answer next. We still have a lot of questions.” Among those is why this mechanism doesn’t seem to work after development is complete. “If the spinal cord is injured, why doesn’t it re-cross that boundary?” she says. “Why are these molecules not functioning well in the adult?” Focal adhesion kinase already is a hot topic among scientists studying how cells migrate and how tumor cells spread. Now, Dr. Xiong and her collaborators have found the enzyme also plays an important role in central nervous system development. She explains that for axons to journey across the spinal cord, floor plate cells along this natural midline of the developing body secrete a guidance or cue factor called netrin-1. “If this molecule is deleted, this axon cannot cross. It just stays on this side” and the developing embryo will die, a testimony to netrin’s expansive role in getting cells where they need to be. “This factor plays a critical role for nearly all the neurons to cross the midline, even in the cortex or hippocampus of the brain,” Dr. Xiong says. A receptor on the axon called DCC, or Deleted in Colon Cancer, responds to the signal from netrin. But why the axon knows to move in a certain direction once it sees that signal was an unknown, Dr. Xiong says. The researchers have now found that once this receptor binds to netrin, focal adhesion kinase is activated that tells the axon to reorganize its structure or cytoskeleton and the restructured axon knows how to move. When they delete the kinase, the axon doesn’t make the proper journey or the proper connection. Developing axons can sense and navigate their environment but how the two functions work together to result in the axon getting where it needs to be is poorly understood, Dr. Xiong says. “Everybody in the developmental neurobiology field is wondering what is the mechanism, how the neuron, once it senses the environment, couples with the motor activity. This provides information for that kind of puzzle,” she says of the newly published work. The researchers are looking for other molecules that also play a role in directing axonal growth. “We have lots of information about how this molecule talks with other molecules,” Dr. Xiong says. “We just need to get a system to figure out how they talk to each other.” She’s also moving toward an injury model to see what happens to this molecular talk after a spinal cord injury. “We know this factor can turn on but we don’t know how it turns on. If you sever the spinal cord, the important crossing of the axon is gone. Right now, we don’t know how to make it go back.” Drs. Xiong’s MCG collaborators on the study include her husband, Dr. Lin Mei, also a developmental neurobiologist; research technician Zhu Feng and graduate student Qiang Wang as well as researchers at the University of Alabama at Birmingham; Johns Hopkins University School of Medicine; and Washington University School of Medicine. Her research is funded by the National Institutes of Health

Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. Yick LW, So KF, Cheung PT, Wu WT. Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong. After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.

he protein EPHA4 might not sound like anything special but its discovery could mean the hundreds of people who suffer spinal cord injuries each year do not have to spend the rest of their lives in a wheelchair. Researchers at the University of Queensland, in collaboration with the University of Melbourne, announced yesterday that they had identified EPHA4 as the molecule that blocks damaged nerves in the spinal cord from regenerating. Scientists had suspected one of a number of molecules was inhibiting the recovery process, but did not know which one. "This looks like it might be the most important molecule discovered to date," said Perry Bartlett, director of UQ's Queensland Brain Institute. "We're fairly excited about it, to say the least." http://www.smh.com.au/articles/2004/09/17/1095394005618.html?oneclick=true

Extreme stretch growth of axons 08 Sep 2004 Researchers at the University of Pennsylvania School of Medicine have induced nerve fibers – or axons – to grow at rates and lengths far exceeding what has been previously observed. To mimic extreme examples in nature and learn more about neuronal physiology, they have mechanically stretched axons at rates of eight millimeters per day, reaching lengths of up to ten centimeters without breaking. This new work has implications for spinal cord and nerve-damage therapy, since longer implantable axons are necessary for this type of repair. In the present study, the team, led by Douglas H. Smith, MD, Professor of Neurosurgery and Director of the Center for Brain Injury and Repair, placed neurons from rat dorsal root ganglia (clusters of nerves just outside the spinal cord) on nutrient- filled plastic plates. Axons sprouted from the neurons on each plate and connected with neurons on the other plate. The plates were then slowly pulled apart over a series of days, aided by a precise computer-controlled motor system. "By rapid and continuous stretching, we end up with huge bundles of axons that are visible to the eye," says Smith. The axons started at an invisible 100 microns and have been stretched to 10 centimeters in less than two weeks. Smith and colleagues report their findings in the cover story of the September 8, 2004 issue of the Journal of Neuroscience. "This type of stretch growth of axons is really a new perspective," says Smith. Despite the extreme growth in length, the axons substantially increased in diameter as well. Using electron microscopy, they confirmed this growth by identifying a fully formed internal skeleton and a full complement of cellular structures called organelles in the stretched axons. "Surprisingly, the axon appears to be invigorated by this extreme growth," says Smith. "It doesn't disconnect, but forms a completely normal-appearing internal structure." These extreme rates of growth are not consistent with the current understanding of the limitations of axon growth. "Proteins necessary to sustain this growth are somehow correctly brought to sites along the axon faster than conceivable rates of transport," notes Smith. The team suggests two possible mechanisms to explain this: increasing transport to a very fast rate or making the necessary proteins at the site, proximal to the growing axons. Smith believes that this form of growth commonly occurs in nature. "For example, it can be inferred that axons in a blue whale's spine grow more than three centimeters a day and in a giraffe's neck at two centimeters a day at peak growth." The team also found that they had to condition the axons to grow in an extreme way. "Although they can handle enormous growth, you can't just spring it on them," explains Bryan Pfister, PhD a post-doctoral fellow in Smith's lab and coauthor of the study. "If we ramp up the stretch rate too fast, the axons will snap." From this the team surmises that in nature animals must grow at a metered pace, which allows for constant feedback and conditioning. It has been well established that axons initially grow out from neurons and follow a chemical stimulus to connect with another neuron. However, once the axon has reached its target a relatively unknown form of stretch-growth must ensue as the animal grows. Mechanical changes in the growing brain, spine, and other bones are the starting point for natural stretch-growth in axons. "We know that it's not tension on the neuron itself, but tension on the axon," says Smith. "It's deformation, a pulling on the axon." At this point, it is unclear what receptors and cell signaling pathways are involved to get the process started, but from this and previous studies the investigators do report that the signal is from a mechanical stimulus along the length of the axon as opposed to a chemical stimulus. "The stretch is coming from the whole body growing," explains Smith. "For example, the growing spine bones in the whale likely exert mechanical forces on the axons in the spinal cord." The researchers conclude that this is a genetic program for growth that has been conserved throughout animal species, but just hasn't been studied in depth. By revealing the mechanisms of extreme-stretch growth, the team is currently applying this knowledge to develop nerve constructs to repair nerve and spinal cord damage. "To find that tension is actually good for your nerves for both growth and repair may not be such a long stretch," says Smith. Penn colleagues on the paper are: Akira Iwata and David F. Meany. This research was funded by the National Institutes of Health. For a copy of the paper, please contact Dawn McCoy or Elissa Petruzzi at the Society for Neuroscience at 202-462-6688. For permission to use images within the paper, please contact Lionel Megino at the Society at lionel@sfn.org. This release can also be found at: http://www.uphs.upenn.edu/news. PENN Medicine is a $2.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation's first integrated academic health system). Penn's School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine. The University of Pennsylvania Health System includes three owned hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice. Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania Medical Center

May lead to treatment for severed spinal cords University of Toronto researchers have designed a method to facilitate nerve cell repair that could ultimately lead to treating severed spinal cords. The technique, outlined in the July 6 online version of Biomaterials, involves imbedding a series of fibrous rods into a gel substance and then dissolving the rods, leaving a series of longitudinal channels. These channels are then injected with peptides, molecules that stimulate cell adhesion and migration. "When nerve cells are placed at the opening of the channel, the peptides act like breadcrumbs to follow," says Molly Shoichet, lead author and professor of chemical engineering and applied chemistry at U of T's Institute for Biomaterials and Biomedical Engineering (IBBME). http://www.eurekalert.org/pub_releases/2004-08/uot-nc081604.php

Over the years, many questions recur repeatedly every few days. Let me try to recap some of these questions to stimulate discussion. Please ask and comment... 1. Will there be a cure for spinal cord injury? • The answer to this question of course depend on one's definition of a cure. If a cure means eradication of spinal cord injury, I think that it is unlikely in my lifetime. If a cure means complete restoration of all function to "normal" or pre-injury levels for all people with spinal cord injury, I think that that this is unlikely because we probably will not have therapies that can completely reverse aging and changes of the body due to the injury. On the other hand, I believe that there will be effective therapies that will restore function to people with spinal cord injury, including touch and pain sensations, bladder and bowel function, erection and ejaculation, and motor control including long-distance walking. Several years ago, I tried to get around the problem of the definition of "cure" by proposing that a person would be cured if a well-informed observer cannot tell that a person has had spinal cord injury. This does not necessarily mean that the person has been completely restored to pre-injury levels or all functions are normal. 2. When will a cure be available? • Some therapies are restoring substantial function to some people. These are what I call the first generation therapies which include treatments like weight-supported treadmill ambulation training, decompression and untethering of a spinal cord that is compressed. Some preliminary data suggest that certain cell transplants such as olfactory ensheathing glia transplants will restore 4-8 levels of sensory function and 1-2 levels of motor function. None of these therapies can be construed as a cure. Second generation therapies are beginning to come into clinical trial and should be available in a few years. These include nasal mucosa olfactory ensheathing glia, Schwann cell transplants, and perhaps even embryonic stem cells. The latter unfortunately have been mired in political debate and has already been delayed by 4 years. In addition, several therapies such as Nogo receptor blockers and Nogo antibodies, glial-derived neurotrophic factor, chondroitinase, and other treatments are being developed for clinical trial and may come on line within a year or two. The timing of such treatments depends on the availability of funding for clinical trials. But, if sufficient funding were available, I think that some of these treatments will be shown to be effective and will be available in 4 years. Finally, third generation therapies will be closer to the "cure". These include possible combination cell transplant therapies with growth factors and other treatments that stimulate regeneration of the spinal cord. These should produce more recovery in more people. For example, cell transplants combined with drugs such as glial-derived neurotrophic factor, chondroitinase ABC, and cAMP/rolipram have been reported to produce significantly better regeneration in rats compared to individual treatments. The rate at which these treatments get into clinical trial depend on the amount of funding available for clinical trial. If funding were made available, I think that some of third generation therapies will be available as soon as 8 years from now. 3. Will a cure work for chronic spinal cord injury? • Yes, I believe so for the following reasons. First, much animal and human data suggest that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Probably about 10% of the axons in the spinal cord are necessary and sufficient to restore some of these functions. Second, animal studies suggest that axons continue to try to regrow for long periods of time after injury. Treatments that provide a path for growth, that negate some of the factors that inhibit growth, and that stimulate axonal growth can restore function. Third, while chronic spinal cord injury studies in animals are still very limited, the fact that many people continue to recover some function years after injury provide hope that these therapies will also work in chronic spinal cord injury. However, it is important to provide some caveats concerning recovery. Recovery may be limited by muscle atrophy and other changes in the body. Likewise, there is a phenomenon called "learned non-use" where neural circuits may turn off after prolonged periods of non-use. Intensive exercise and physical therapy will be necessary to reverse these changes. 4. What can I do now to be ready for the cure? • The first and foremost concern of people with spinal cord injury should be to take care of their body and try to prevent muscle and bone atrophy and other changes that may prevent recovery of function. This is difficult but people need to engage in disciplined exercise that maintains their muscle and bone, take care of their skin, bladder, and bowels. People should avoid procedures that cause irreversible loss of peripheral nerve and other functions. On the other hand, it is important to weigh the benefits of procedures such as tendon transfers which can provide greater functionality and independence for people with weak hands. Likewise, certain procedures such as Mitrofanoff and bladder augmentation to reduce bladder spasticity may provide greater independence but may not be easily reversible. Finally, many studies have shown that people with the highest levels of education after injury are more likely to have better quality of life and health. It is important that people do not neglect their brain, the most important part of their body. 5. What can I do about spasticity, spasms, and neuropathic pain? • Many people suffer from spasticity (increased tone), spasms (spontaneous movements), and pain or abnormal sensations (in areas below the injury site where there is diminished or absent sensation). These problems arise from disconnection of the brain from the body. Neurons in the spinal cord that have been disconnected tend to become hyperexcitable. Spasticity is the most common manifestation. Several treatments will reduce spasticity. The most commonly used drug is baclofen (a drug that stimulates GABA-B receptors in the spinal cord). Oral doses of baclofen up to 120 mg/day will reduce spasticity for most people. However, due to side-effects, some people cannot tolerate high oral doses and must take combinations of drugs, including clonidine or tizanidine which activate alpha-adrenergic receptors. In general, while these drugs reduce spasticity, they are typically not effective in preventing spasms without causing significant weakness. Taking too much anti-spasticity drug may reduce the muscle tone to the extent that muscle atrophy will occur. So, people should titrate the dose of anti-spasticity drugs so that they continue to have some tone. Few drugs are effective against spasms. One possible drug is neurontin (gabapentin) which is an anti-epileptic drug. Neuropathic pain probably results from increased excitability of spinal neurons that have been disconnected from sensory signals and may manifest in "burning", "freezing", or "pressure" type pain, usually in areas where normal sensation is absent or greatly diminished. Neurontin is reduces neuropathic pain in some people but people generally accomodate to the drug and higher doses are necessary over time. In some people, low doses (20 mg/day) of the anti-depressant drug amitryptaline (Elavil) may be useful in taking the edge off neuropathic pain. However, for many people, none of the oral drugs are sufficient to control spasticity, spasms, or neuropathic pain. For people with severe spasticity, a pump that delivers baclofen directly to the spinal cord through an implanted catheter may be effective and necessary. In about 15% of people, however, none of these therapies are sufficient to control spasms and neuropathic pain. 6. How can I exercise and will it do any good? • Exercise in a paralyzed person is difficult and some specialized equipment may be necessary and useful for exercising the muscles. First, most people have standing frames where they can stand for an hour or two every day. Second, functional electrical stimulation (FES) can be used to activate their leg muscles and the legs can be stimulated to pedal an exercise bike. Third, standing and walking in a swimming pool is the cheapest and possibly most cost-effective way for a person to stand and walk. Fourth, weight-supported treadmill ambulation training has been shown to improve walking recovery. Finally, people should think about setting aside a month or two every year where they would essentially engage in full-time training. During the rest of the year, they need to maintain the gains that they have achieved by spending an hour or so per day on exercising. Although there have been few formal studies of the subject, many people with spinal cord injury have reported significant increases in the girth of their legs when they use FES regularly. 7. What is osteoporosis, its mechanisms and consequences, and ways to reverse it? • Osteoporosis is loss of calcium in bone that occur throughout the skeletal system, particularly in the pelvis and legs below the injury site. The mechanism is not understood but appears to be related to disuse and the loss of gravitational and other stresses on the bone. In acute spinal cord injury, bone begins to decalcify within days after spinal cord injury, with significant increases in calcium in the urine (hypercalciuria) within 10 days. The pattern of bone loss is 2-4 times greater those seen in people on prolonged bedrest without spinal cord injury, similar to the bone loss seen in postmenopausal women. The loss of bone is not effectively reversed by increased dietary calcium intake alone. Parathyroid hormone level is generally low in the first year but increases above normal after the first year. Substantial (25-43%) decreases in bone mineral densities occur in the leg bones occur within a year and may exceed 50% loss by 10 years while bone density may increase in the arms after 4 months in paraplegic patients, compared to tetraplegics. Some studies suggest that people with spasticity have less bone loss than those who are flaccid. Losses in bone result in increased fracture rates. The Model Spinal Cord Injury System, for example, reported a 14% incidence of fracture by 5 years after injury, 28% and 39% by 10 and 15 years, usually in the most demineralized bone. People with complete spinal cord injury and paraplegia have 10 times greater fracture rates than those with incomplete injury or tetraplegia. Weight-bearing and bicycling with functional electrical stimulation will reverse osteoporosis when started within 6 weeks after injury. However, such programs are less effective in people with chronic spinal cord injury. Some preliminary studies suggest that treatment bisphosphonates (Pamidronate) and parathyroid hormone (Teriparatide) can prevent or reduce osteoporosis and fracture rates in people with chronic spinal cord injury. http://www.emedicine.com/pmr/topic96.htm 8. What is autonomic dysreflexia, its mechanisms and consequences, and treatments? • Autonomic dysreflexia (AD) refers to increased activity of the sympathetic nervous system, associated with profuse sweating, rash, elevated blood pressure, and vasodilation above the injury level. People with AD commonly develop a headache caused by vasodilation of brain blood vessels. Heart rate falls and vision may be blurred. Nasal congestion may be present. Between 40-90% of people with spinal cord injury suffer from AD and is more severe in people with spinal cord injury above T6. AD can be triggered by many potential causes, including bladder distension, urinary tract infection, and manipulation of the bowel and bladder system, pain from any source, menstruation, labor and delivery, sexual intercourse, temperature changes, constrictive clothing, sunburns, and insect bites. When AD occurs, doctors usually catheterize the bladder to ensure adequate urinary drainage, check for fecal impaction manually using lidocaine jelly as a lubricant, and eliminate all other potential causes of irritation to the body. Treatment includes use of calcium channel blocker Nifedipine (Procardia 10 mg capsule) to reduce blood pressure or adrenergic alpha-receptor blocking agent phenoxybenzamine (10 mg twice a day), mecamylamine (Inversine 2.5 mg orally). Diazoxide (Hyperstat 1-3 mg/kg). Often doctors in emergency room may not know how to handle AD crises in people with spinal cord injury and therefore it is important for people to know the treatments. http://www.emedicine.com/pmr/topic217.htm 9. What is syringomyelia, its mechanisms and consequences, and treatments? • Syringomyelia is the presence of a cyst in the spinal cord, resulting from enlargement of the central canal. The central canal is typically tiny and not visible on magnetic resonance images (MRI) of the spinal cord. As many as 15% of people develop a syringomyelic cyst in their spinal cords with perhaps 5% showing symptoms of pain and loss of function associated with cyst enlargement, beginning as early as one month to as late as 45 years after injury. Pain is the most commonly reported symptom associated with syringomyelia. Other symptoms include increased weakness, loss of sensation, greater spasticity, and increased sweating. The symptoms can be aggravated by postural changes, Valsalva manuever (increasing pressure in the chest). It may also be associated with changes in bladder reflexes, autonomic dysreflexia, painless joint deformity or swelling, increased spasticity, dissociation of sensation and temperature, respiratory impairment. The cyst can be observed with MRI scans. It is usually associated with scarring of the meninges or arachnoid membranes of the spinal cord, observable with CT-scan with myelography. Surgical intervention is recommended when there is progressive neurological loss. Traditionally, syringomyelia has been treated with shunting of the cyst by placement of a catheter between the cyst and the subarachnoid space or pleural cavity. But shunting alone is frequently associated with shunt blockade within a year. More recent studies suggest that meticulous removal of adhesions with duroplasty (increasing the dura by grafting membrane) to re-establish subarachnoid cerebrospinal fluid flow is more effective and may result in elimination of the cyst in 80% of cases. One study has shown that transplantation of fetal tissues into the cyst can eliminate the cyst. http://www.emedicine.com/pmr/topic115.htm 10. What is the effect of spinal cord injury on sexual function and what can be done to improve such function? • Most people with spinal cord injury above the T10 will continue to have reflex erections associated with stimulation. Some people may have prolonged erections called priapism. A majority can have ejaculation although increased stimulation including vibration may be required. In many people, ejaculation may be retrograde, i.e. the ejaculate goes into the bladder rather comes out, because the external sphincter may be open. Retrograde ejaculation should not be harmful or cause urinary tract infections. A serious associated complication of sexual intercourse in both men and women is the occurrence of autonomic dysreflexia (AD) with orgasm, with associated headaches and other symptoms of AD. These can be treated with drugs to lower blood pressure (see answer to AD above). In addition, sexual intercourse may be associated with increased spasticity and spasms. People with injuries below T10 may have damage to the spinal cord centers responsible for erection and ejaculation. Many techniques are available to increase erection, including drugs such as Sildenafil (Viagra), vacuum pumps, cock rings, and penile prostheses. Several studies have reported that women with "complete" spinal cord injury can achieve orgasms, possibly through neural pathways outside of the spinal cord. Wise Young Ph.D. M.D WM Keck Center of Collaborative Neuroscience Rutgers University

Nerve Cells Successfully Regenerated Following Spinal Cord Injury Libraries Science News Keywords CELL GRAFTS AXONS REGENERATION COMBINATIONAL THERAPY Contact Information Available for logged-in reporters only Description Using a combination of therapies and cell grafts, a team of researchers has promoted significant regeneration of nerve cells in rats with spinal cord injury. Journal of Neuroscience Embargo: 5:00 p.m. ET, Tuesday, July 13, 2004 Nerve Cells Successfully Regenerated Following Spinal Cord Injury Newswise — Using a combination of therapies and cell grafts, a team of University of California, San Diego (UCSD) School of Medicine researchers has promoted significant regeneration of nerve cells in rats with spinal cord injury. The therapeutic approach successfully stimulated new nerve fibers called axons to grow and extend well beyond the site of the injury into surrounding tissue, following surgically induced spinal cord damage. These results prove that combinational therapy can promote the vigorous growth of new axons even after a complete lesion of the spinal cord cells, with the new growth extending through implanted tissue grafts, and into the spinal cord and healthy tissue surrounding the injury site, according to Mark Tuszynski, M.D., Ph.D., professor of neurosciences at UCSD and senior author of the study. The paper is published in the July 14 issue of the Journal of Neurosciences. “Previous studies have demonstrated reduced lesion and scarring, tissue sparing and functional recovery after acute spinal cord injury,” said Tuszynski, who also has an appointment with the Veterans Affairs Medical Center, San Diego. “This study shows unequivocally that axons can be stimulated to regenerate into a cell graft placed in a lesion site, and out again, into the spinal cord -- the potential basis for putting together a practical therapy.” http://www.newswise.com/articles/view/505973/

http://www.betterhumans.com/News/news.aspx?articleID=2004-07-13-2 quote: Antibody Block Helps Regenerate Spinal Cord Concentrated medicine neutralizes effects of potent nerve growth inhibitor By Gabe Romain Betterhumans Staff 7/13/2004 3:26 PM An antibody treatment that neutralizes a nerve growth inhibitor has repaired damaged spinal cords in rats and could do the same in humans. Researcher Lisa Schnell and colleagues at the Brain Research Institute in Zurich, Switzerland have found that Nogo, a potent central nervous system growth inhibitor, can be neutralized by antibodies in animal models of spinal cord damage, and have now used this knowledge to develop a treatment method that could be applied in people. "We first managed to successfully regenerate fibers in the spinal cord of an adult animal's central nervous system as long ago as 1990, but this involved implanting cells directly into the brain to secrete antibodies, which is not something you want to do as a routine treatment for people," says Schnell. "Since then we have purified the antibodies and developed ways to produce enough of them to use as a medicine." Inhibitory protein Nogo (for "neurite outgrowth inhibitor") is a protein that inhibits the regeneration of axons after central nervous system injury. Axons are the telephone lines of the nervous system, carrying nerve impulses along the brain and spinal cord. It is thought that myelin is responsible for the inability of axons to regenerate following injury. Myelin is an electrically insulating fat that forms a sheath around axons and speeds the transmission of impulses along nerve cells. Researchers have theorized that myelin locks an adult's fully formed neural network in place, preventing the development of new and potentially harmful circuits. This protective mechanism, however, prevents nerve cells from repairing themselves when damaged. "The problem with repair systems is that they can overshoot, which could leave you with the wrong connection so that you want to move your arm but your leg moves instead, or you might get terrible constant pains," says Schnell. "The Nogo protein system may be there to protect us from any of these mistakes. But of course that gives us a problem if we get injured." Anti-Nogo Antibodies, used by the immune system to identify and neutralize foreign objects, can also be used in medicine to target specific objects such as cancer cells. By inserting very fine tubes under the membrane that surrounds the brain and spinal cord, Schnell and colleagues have now been able to deliver concentrated Nogo antibodies directly to damaged areas in the spinal cords of rats. After treatment, the rats performed well on a series of motor tests. In addition, anatomical analysis of the Nogo-neutralized rats showed increased sprouting and long distance regeneration of axons. Once the anti-Nogo system is shown to be safe in other animal models, the first human patients with spinal cord injuries will be considered for treatment. "The first patients we would try this technique on would probably be recently injured young men and women with severe injuries who have no hope of spontaneous recovery," says Schnell.

Nerve Cells Successfully Regenerated Following Spinal Cord Injury Libraries Science News Keywords CELL GRAFTS AXONS REGENERATION COMBINATIONAL THERAPY Contact Information Available for logged-in reporters only Description Using a combination of therapies and cell grafts, a team of researchers has promoted significant regeneration of nerve cells in rats with spinal cord injury. Journal of Neuroscience Embargo: 5:00 p.m. ET, Tuesday, July 13, 2004 Nerve Cells Successfully Regenerated Following Spinal Cord Injury Newswise — Using a combination of therapies and cell grafts, a team of University of California, San Diego (UCSD) School of Medicine researchers has promoted significant regeneration of nerve cells in rats with spinal cord injury. The therapeutic approach successfully stimulated new nerve fibers called axons to grow and extend well beyond the site of the injury into surrounding tissue, following surgically induced spinal cord damage. These results prove that combinational therapy can promote the vigorous growth of new axons even after a complete lesion of the spinal cord cells, with the new growth extending through implanted tissue grafts, and into the spinal cord and healthy tissue surrounding the injury site, according to Mark Tuszynski, M.D., Ph.D., professor of neurosciences at UCSD and senior author of the study. The paper is published in the July 14 issue of the Journal of Neurosciences. “Previous studies have demonstrated reduced lesion and scarring, tissue sparing and functional recovery after acute spinal cord injury,” said Tuszynski, who also has an appointment with the Veterans Affairs Medical Center, San Diego. “This study shows unequivocally that axons can be stimulated to regenerate into a cell graft placed in a lesion site, and out again, into the spinal cord -- the potential basis for putting together a practical therapy.” http://www.newswise.com/articles/view/505973/

Proneuron's Phase II, international, multi-center, randomized-controlled study of ProCord, an experimental procedure for complete spinal cord injury is now enrolling in the US and Israel. This study is open to patients who meet eligibility criteria, including but not limited to ASIA Grade A, C5-T11, within 14 days of injury. For additional information on the study, please contact Heather at Heather.Ridgeway@proneuron.com. For immediate attention to participate in this study contact our 24/7 call center at 1-866-539-0767. Please visit www.proneuron.com Heather Ridgeway

http://www.taipeitimes.com/News/taiwan/archives/2004/06/27/2003176694 Local scientists achieve stem cell breakthrough STUDY: Doctors have developed a new approach to cultivating stem cells which they say frees researchers of the ethical problems associated with previous methods By Joy Su STAFF REPORTER Sunday, Jun 27, 2004,Page 2 Amniotic fluid extracted for routine genetic tests performed during pregnancy could be used for stem cell research and tissue engineering, according to a study conducted by local doctors. "We found a way to isolate mesenchymal stem cells [MSCs] from amniotic fluid routinely extracted during the second-trimester amniocentesis by implementing a two-stage culture protocol," said Tsai Ming-sing (蔡明松), a doctor at the Prenatal Diagnosis Center of the Cathay General Hospital's department of obstetrics and gynecology. According to Tsai, stem cells, which are capable of replicating into different kinds of tissues, including bone, cartilage, fat, tendon, muscle and even neuron-like cells, are most commonly extracted from adult bone marrow and embryonic tissues or organs. These stem cells could possibly be used to treat heart disease, diabetes, stroke and spinal and head injuries, among other uses. "MSCs could be used to repair many injuries and diseases. Neurological injuries, head injuries, Alzheimer's, Parkinson's -- treatment for these conditions will be the focus of future research plans," Tsai told the Taipei Times yesterday. Given Tsai's latest findings, women receiving second-trimester amniocentesis, a procedure during which a sample of the fluid surrounding a fetus is extracted for the purpose of identifying genetic mutations and characteristics such as sex, could be the key to collecting MSCs. "We've found a way to cultivate the MSCs from the amniotic fluid without interfering with the routine process of fetal karyotyping," Tsai said. Karyotyping is a commonly used technique used to study the appearance of chromosomes during genetic diagnosis. Tsai yesterday explained the advantages that his research findings had over other methods of harvesting and cultivating MSCs. "Because the extraction of MSCs from prenatal tissues and organs often lead to abortion, embryonic stem cell research faces many difficult ethical problems. However, MSCs derived from amniotic fluid are free of these ethical questions," Tsai said. He said that extracting the cells from amniotic fluid bypasses the problems associated with a technique called donor-recipient HLA matching, which involves trans-planting bone-marrow stem cells. "This opens a new avenue for ... fetal gene and cellular therapies without inducing tissue rejection," Tsai writes in an article published in this month's edition of the medical journal Human Reproduction. The journal features a picture of MSCs studied in Tsai's project on its cover. While current technology allows scientists to collect amniotic fluid through the cervix, Tsai said that this could lead to the possible premature termination of pregnancy and contamination by the mother's blood. According to Tsai, a significantly larger amniotic fluid culture could be collected utilizing second-trimester amniocentesis. "With amniotic fluid cells, it takes 20 to 24 hours to double the number of cells collected. The doubling time for [umbilical] cord stem cell is 28 to 30 hours. Bone marrow takes over 30 hours. With urgent medical conditions, speed could be crucial," Tsai said. In addition, while scientists have only been able to isolate and differentiate on average just 30 percent of MSCs extracted from a child's umbilical cord shortly after birth, the success rate for amniotic fluid-derived MSCs is close to 100 percent, according to Tsai.

Compound Discovered by Curis Promotes Development of Motoneurons

06/16/04 -- Curis, Inc. (NASDAQ: CRIS), a therapeutic drug development company, today announced that the recent issue of the Proceedings of the National Academy of Science USA contains an article that describes the use of a small molecule Hedgehog signaling pathway agonist to promote the generation of new motoneurons. Motoneurons are nerve cells that are most typically found in the spinal cord, and their purpose is to establish functional connections with other tissues, usually muscles, to control movement and other functions. Damage to motoneurons can occur as result of injury, such as spinal cord injury, or as a result of disease, such as amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease.

The scientific publication is entitled "Axonal Growth of Embryonic Stem Cell-derived Motoneurons in vitro and in Motoneuron-injured Adult Rats." The report states that isolated stem cells can be converted into motoneurons when these cells are exposed to a Hedgehog agonist and another compound called retinoic acid. Because these new motoneurons are very similar to true motoneurons, they are believed to have potential therapeutic utility as replacement cells to reconstitute damaged neural systems.

Dr. Lee Rubin, Curis' Chief Scientific Officer, said, "The Hedgehog signaling pathway regulates the normal development and growth of several tissues and organs, including tissues of the nervous system. This study confirms that activation of the Hedgehog pathway can have a significant positive impact on the production of new motoneurons. We believe that Hedgehog pathway agonists may have real therapeutic potential when used directly to promote the development of new neurons in the body. Many of the small molecule Hedgehog agonists that we have developed are orally available and in principle could be administered in a pill formulation."

In January 2004, Curis entered into an agreement to license Hedgehog pathway agonist technologies to Wyeth Pharmaceuticals, a division of Wyeth (NYSE: WYE - News) on an exclusive worldwide, royalty-bearing basis. The agreement provides for the development and commercialization of pharmaceutical products based on these technologies for therapeutic applications in treatment of neurological disorders, such as spinal cord injury, Parkinson's disease, ALS, and other disorders.

About Curis, Inc.

Curis, Inc. is a therapeutic drug development company. The Company's technology focus is on regulatory pathways that control repair and regeneration. Curis' product development involves the use of proteins or small molecules to modulate these pathways. Curis has successfully used this technology and product development approach to produce several promising drug product candidates in the fields of kidney disease, neurological disorders, cancer, alopecia, and cardiovascular disease. For more information, please visit the Curis web site at www.curis.com.

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements about Curis' drug discovery and development programs. Such statements may contain the words "believes", "expects", "anticipates", "plans", "seeks", "estimates" or similar expressions. These forward looking statements are not guarantees of future performance and involve risks, uncertainties, assumptions and other factors that may cause Curis' actual results to be materially different from those indicated by such forward-looking statements. Actual results can be affected by a number of important factors including, among other things: adverse results in Curis' and its strategic partners' product development programs; difficulties or delays in obtaining or maintaining required regulatory approvals; Curis' ability to obtain or maintain the patent and other proprietary intellectual property protection necessary for the development and commercialization of products based on its technologies; changes in or Curis' inability to execute its realigned business strategy; the risk that Curis does not obtain the additional funding required to conduct research and development of its product candidates and execute on its business plan; unplanned cash requirements and expenditures; risks relating to Curis' ability to enter into and maintain important strategic partnerships, including its ability to maintain its current collaboration agreements with Genentech, Ortho and Wyeth; the risk that competitors will discover and develop signaling pathway-based therapeutics faster and more successfully that Curis and its collaborators are able to; and other risk factors identified in Curis' most recent Annual Report on Form 10-K, Quarterly Report on 10-Q and any subsequent reports filed with the Securities and Exchange Commission. In addition, any forward-looking statements represent the Company's views only as of today and should not be relied upon as representing its views as of any subsequent date. Curis disclaims any intention or obligation to update any of the forward-looking statements after the date of this press release whether as a result of new information, future events or otherwise.

Source: Curis, Inc.

posted 06-02-02 09:16 AM
Brainland – The Neuroscience Information Center

http://www.brainland.com/

http://www.brainland.com/indiv_news.cfm?ID=396

Human olfactory mucosa grafts in traumatic spinal cord injuries: a way to cure paralysis?

By carlos lima, Hospital Egas Moniz- Lisbon- Portugal

Recent published articles showed that transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. A medical team at the Hospital Egas Moniz, in Lisbon- Portugal has performed for the first time in humans, an autologous graft of olfactory mucosa at the injured spinal cord in 3 patients. The first procedure was performed at 2001, July with the transplant with olfactory mucosa to a six month cervical (C7, T1) cyst contusion type lesion (complete transverse section) from a female patient with 21 years old. The surgery time was about four hours. There were no complications ( no fever, no infections or other side effects) and four days after the patient was discharged. She started to have some sensory recovery about 1 month later and 2 months later she started to have voluntary control on abdominal muscles. Two month ago she started to have voluntary control at the gluteos and left leg adutor muscles and stands up by both legs without any devices on it. The NMR 3 months after the operation showed a filling and continuity of the graft within the cavity. Three months after the operation olfaction was completely recovered. The two others patients wait for results since they were operated within the last month. In theory the graft furnished stem cells (olfactory basal cells), neurons, schwann cells and olfactory ensheathing cells with putative potential for regeneration and may prove to become a reliable method to cure paralysis.

The Spinal Cord Society (SCS) is sponsoring a pre-Phase 1 human clinical trial to produce a cure for chronic spinal cord injury paralysis.......

http://www.lionsclubtraralgon.asn.au/scr.html

News / 15 December 2003

Oxford BioMedica Presents Proof-of-Principle Data for its Innurex™ Nerve Repair Programme at the 10th International Symposium on Neural Regeneration

Oxford BioMedica announced today that interim preclinical data from the Innurex™ nerve repair programme are being presented by Prof. Malcolm Maden of King's College London at the 10th International Symposium on Neural Regeneration which is being held at the Asilomar Conference Center, Pacific Grove, California. The data, which will shortly be sent for peer-reviewed publication, show that Innurex™ is able to induce nerve regrowth at the site of injury in a model of nerve damage. These results strongly support the technical principle of Innurex™, which is designed for nerve repair and the treatment of spinal injury.

Within the field of neurobiology nerve repair has been a long sought goal for the treatment of nerve damage and spinal injury. The aim is to induce nerve cells to regrow and bridge sites of injury thereby reconnecting the nerve fibres and restoring function. Results obtained to date by other groups based on different mechanisms of nerve repair have shown only inefficient induction of regrowth of nerves and very limited restoration of function.

Innurex™ is a product comprising Oxford BioMedica's LentiVector delivery system carrying the RARß2 gene. The Company acquired exclusive rights to the RARß2 gene from King's College London where the initial observation that this gene could programme nerve cells to regrow in vitro was made. The new data are the first in vivo data to come from the Innurex™ programme and they indicate that Innurex™ has the potential to be a first-in-class product for nerve repair.

Commenting on the results Prof. Maden said "The combination of the RARß2 gene and the very efficient LentiVector delivery system has produced a high level of axon (nerve) regrowth. There is every chance that this is enough for restoration of function to damaged nerves and the Company should have functional data shortly".

Prof. Alan Kingsman, Oxford BioMedica's Chief Executive said "The Innurex™ programme has gone from initial observation to proof of principle in a good animal model in less than two years. This is a remarkable achievement by the King's team and the Oxford BioMedica staff. Innurex™ is on course for clinical development within the next 12 months".

Oxford BioMedica, the gene therapy company, will on Monday announce what it says are the best results anyone in the world has achieved in animal experiments to repair damaged nerves.

Overview - Gene therapy: A rollercoaster ride of hopes and upsets

Financial Times

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Oxford Bio to reveal results on nerve repair
By Clive Cookson, Science Editor
Published: December 14 2003 21:54 | Last Updated: December 14 2003 21:54

Oxford BioMedica, the gene therapy company, will on Monday announce what it says are the best results anyone in the world has achieved in animal experiments to repair damaged nerves.

The data will put the Oxford-based company in a strong position in the race to produce an effective treatment for spinal injury and restore movement to paralysed limbs.

First animal test results for Innurex, Oxford Bio Medica's nerve regeneration product, will be given to a scientific conference in California by an academic collaborator, Prof Malcolm Maden of King's College London. They show "a high level of nerve regrowth" in injured mice.

Alan Kingsman, the company's chief executive, said: "We are seeing neurites, the initial stage of nerve regrowth, bridging the injury gap, at an efficiency that no one has achieved before."

Nerve repair is an extremely active field of research, with scientists throughout the world testing various biological methods to get neurones to bridge the site of an injury and reconnect nerve fibres, so that function is restored.

Christopher Reeve, the Hollywood actor paralysed after a riding accident in 1995, has catalysed the field with his determination to recover and his support for research that might help him to do so.

However, results have generally been disappointing. Several animal experiments that had given excellent preliminary data were not reproducible.

Much research into nerve repair involves transplanting cells - neurones or their precursors - from elsewhere to the site of injury. Oxford BioMedica and King's have a different approach - gene therapy. Innurex uses a virus to carry a gene called RARbeta2 to nerve cells at the injury site; this induces them to sprout new nerve connections.

But the new animal data have not yet been published in a peer-reviewed scientific journal and, in view of past disappointments in spinal injury research, no one will be pinning their hopes on Innurex as an effective treatment until it has been tested more thoroughly.

Oxford BioMedica expects to release more extensive animal data in the spring, showing the extent to which Innurex has restored movement to mice that have been partially paralysed.

If these results are as good as Monday's preliminary data, the company will plan a clinical trial, though this could not take place before 2005.

Innurex is likely to work best when injected by a surgeon directly into the site of a fresh spinal injury, so that nerve growth can be stimulated before scarring sets in. Restoring movement to people such as Mr Reeve, who have been paralysedfor years, is a greater challenge.

The annual potential market for a treatment could be $500m-$2bn (Ł287m-Ł1.1bn).

Financial Times
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Dr. Young eszrevetele:
This is a very interesting approach. The retinoic acid receptor does a lot of interesting things. This particular study used a lentivirus to insert the gene for retinoic acid receptors (RAR-beta 2) into cells and this apparently is causing either the neurons to regenerate or cells around the neurons to pump out factors that are stimulating regeneration. It is hard to judge from these breathless press releases how good the evidence is and what the degree of regeneration is, what has regenerated, and whether there is functional recovery associated with the treatment. This apparently was done in mice but they do not talk about the model or whether there is recovery associated with the regeneration. This still has to undergo peer-review. So, it is of great interest but it is not yet time to be very excited. Incidentally, it may not be easy to get this particular gene therapy approach approved by the FDA. It is using a lentivirus and so there has to be appropriate safety studies, evidence that this does not cause tumors, etc. But, I think that this is good and I shall post whatever I can find about this study in the near future

Self-Assembling Proteins Could Help Repair Human Tissue
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Researchers have created a class of artificial proteins that can assemble themselves into a gel and encourage the growth of selected cell types. This biomaterial is expected to help scientists who are developing new ways to repair injured or diseased body parts.

Newswise — Johns Hopkins University researchers have created a new class of artificial proteins that can assemble themselves into a gel and encourage the growth of selected cell types. This biomaterial, which can be tailored to send different biological signals to cells, is expected to help scientists who are developing new ways to repair injured or diseased body parts.

“We're trying to give an important new tool to tissue engineers to help them do their work more quickly and efficiently,” said James L. Harden, whose lab team developed the new biomaterial. “We’re the first to produce a self-assembling protein gel that can present several different biological signals to stimulate the growth of cells.”

Harden, an assistant professor in the Department of Chemical and Biomolecular Engineering, reported on his work March 28 in Anaheim, Calif., at the 227th national meeting of the American Chemical Society. His department is within the Whiting School of Engineering at Johns Hopkins.

Tissue engineers use hydrogels, which are macromolecular networks immersed in an aqueous environment, to provide a framework or scaffold upon which to grow cells. These scientists hope to advance their techniques to the point where they can treat medical ailments by growing replacement cartilage, bones, organs and other tissue in the lab or within a human body.

The Harden lab’s new hydrogel is made by mixing specially designed modular proteins in a buffered water solution. Each protein consists of a flexible central coil, containing a bioactive sequence and flanked by helical associating modules on each end. These end-modules come in three distinct types, which are designed to attract each other and form three-member bundles. This bundling leads to the formation of a regular network structure of proteins with three-member junctions linked together by the flexible coil modules. In this way, the new biomaterial assembles itself spontaneously when the protein elements are added to the solution.

The assembly process involves three different “sticky” ends. But between any two ends, Harden can insert one or more bioactive sequences, drawing from a large collection of known sequences. Once the gel has formed, each central bioactive module is capable of presenting a specific biological signal to the tissue engineer’s target cells. Certain signals are needed to encourage the adhesion, proliferation and differentiation of cells in order to form particular types of tissue.

Harden’s goal is to provide a large combinatorial “library” of these genetically engineered proteins. A tissue engineer could then draw from this collection to create a hydrogel for a particular purpose. “We want to let the end-user mix and match the modules to produce different types of hydrogels for selected cell and tissue engineering projects,” he said.

Harden believes this technique may speed up progress in the tissue engineering field. For one thing, tissue engineers would not have to do complex chemistry work to prepare a hydrogel for each specific application; his hydrogels form spontaneously upon mixing with water. Also, unlike hydrogels that are made from synthetic polymers, the Harden team’s hydrogels are made of amino acids, the native building blocks of all proteins within the body. Finally, more than one protein signaling segment can be included in the Harden team’s hydrogel mix, allowing a tissue engineer to send multiple signals to the target cells, thereby supporting the simultaneous growth of several types of cells within one tissue.

“Our philosophy is to take a minimalist approach,” Harden said. “Our hydrogels are designed to send only the growth signals that are needed for a particular application.”

Harden’s colleagues in the hydrogel research are Lixin Mi, who earned his doctorate at Johns Hopkins and now is a postdoctoral researcher at the National Institutes of Health; and Stephen Fischer, a current doctoral student in the Department of Chemical and Biomolecular Engineering.

The Harden team’s research was supported by a grant from NASA through the Program on Human Exploration and Development of Space. Stephen Fischer is also supported by a NASA Graduate Student Researchers Program fellowship.

Related Links:
James Harden’s Web Page: http://www.wse.jhu.edu/chbe/faculty/harden/g
Department of Chemical and Biomolecular Engineering: http://www.jhu.edu/chbe

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http://www.nature.com/nsu/040119/040119-13.html

Self-assembling scaffold for spinal-cord repair
'Liquid' bridge could help severed nerve cells grow.
23 January 2004
HELEN R. PILCHER

Miniature scaffolds give nerves something to grow on.
© Digital Vision

It may well be the smallest scaffolding in the world, and the easiest to set up. Researchers have devised a tiny self-assembling structure that they hope will help repair damaged spinal cords.

Every year in the United States alone, about 15,000 people damage their spines. Few recover fully as it is difficult for damaged nerves to grow across the gap in a severed spinal cord.

Researchers have tried to build bridges across these gaps, so that nerves can grow. Most of these are made out of a solid material such as collagen, but require invasive surgery that can cause extra trauma to the injury.

Samuel Stupp and colleagues from Northwestern University, Chicago have now found a way to build a bridge out of liquid instead1.

When the solution is injected into a damaged rodent spinal cord, it turns into a gel-like solid, says Stupp. The scaffold is designed to disintegrate after four to six weeks, hopefully leaving healthy spinal cord behind.

Self-assembly

The liquid is made up of negatively charged molecules. Normally, they repel one another and keep the substance in liquid form. But when the fluid encounters positively charged molecules - such as the calcium or sodium ions found in living tissue - they clump together. "The effect happens almost instantly," says Stupp.

The molecules are designed to aggregate in a particular way, forming a mass of tiny, hollow tubes. Each tube is about 5 nanometres wide - 10,000 times smaller than the width of a human hair - and several hundreds of nanometres long. The structure is porous, allowing nerve cells to grow through and around it.

The team also laced each molecule in the liquid with a tiny protein fragment that nerve cells can recognize and latch on to. This may aid the development and growth of nerve cells, speculates Stupp.

It's a sophisticated system, says David Mooney, who studies tissue engineering at the University of Michigan. It allows you to control the physical and biological make-up of the structure.

Bridging the gap

But there are many hurdles to overcome. Even with the chemically laced scaffolding in place, nerve cells may still struggle to regrow.

After a spinal-cord injury, the surrounding cells multiply to form a dense scar, explains spinal-cord researcher Elizabeth Bradbury from Kings College London. This barrier is impenetrable to nerve cells, so enzymes that can break it down may also need to be added, she says.

To give spinal-cord repair an extra boost, the team also tried introducing fresh nerve cells into the system. When they added stem cells - cells that can turn into other, specific types of cells, such as nerves - to the scaffolding solution, they turned into neurons and began to grow within the solidified bridge. The team plans to try to do the same thing in damaged rodent spinal cords.

ez nem olyan egyszeru ahogy Nikolett elmondta.
a glialis heg eltavolitasa onmagaban nem eleg.
az inhibitorok blokkolasa-t es a growth cone guidance-t is meg kell oldani.

http://www.tv2.hu/cikk.php?cikk=100000088023
Videon "www.tv2.hu" naplo,marcius 27-ei adas.

Csodaklinika Düsseldorfban
Egy maroknyi kutató a remény városában: gyógyíthatóak lesznek a gerincvelő sérülései

Néhány évvel ezelőtt egy világhíres színész ébredt fel egy klinikai ágyon - és megdöbbenve vette észre, hogy nyaktól lefelé megbénult. A tolókocsiba kényszerült színész - nem más mint Cristopher Reeves - akit addig csak Szupermenként ismert a világ, első kérdése feleségéhez az volt: miért nem hagytál meghalni?

Mégis életben maradt, és él azóta is: és nem sajnálja a dollármilliókat azoktól a kutatásoktól, amik folytán mások nem fognak majd tolószékbe kényszerülni. A csoda hamarosan megtörténhet: egy Düsseldorf-i klinika laboratóriumában már újra képesek járni az elvágott gerincű patkányok. A Napló stábja járt a helyszínen.

Düsseldorfot egy maroknyi kutató a remény városává tette a világ több százezer tolószékbe kényszerült ember számára. Klapka Nikolett, a 29 esztendős magyar származású lány olyan gyógyszert tesztel a laboratóriumi patkányain, ami újra képessé teszi a félig elvágott gerincű állatokat a járásra.

Mint azt a Napló stábjának Nikolett elmagyarázta, a a gerincvelő sérülése azért járt együtt a tragikus bénulással, mert a seb helyén, az idegszálak újra összenőnének ugyan, de ezt a keletkező heg gátolja, az idegsejtek végződései nem érnek össze. Nikolett és munkatársai egy olyan gyógyszert tesztelnek az állatokon, ami a hegesedést lassítja, és esélyt ad az idegsejteknek, hogy keresztülnőjenek a keletkezett szakadáson: a remény abban áll, hogy a gerincvelőnek van esélye meggyógyítani önmagát.

A patkányokon végzett kísérletek tanúsága szerint a kezelt állat mozgáskoordinációja mintegy hatvan százalékkal javul, életlehetőségei jelentősen bővülnek. Nikolett a Napló kérdésére elmondta, hogy a főemlősökön, majd embereken végzett kísérletek engedélyezésére várnak, de a fiatal magyar lány bizakodó: szerinte hét-nyolc éven belül már hozzáférhető lesz a gyógyszer, ami meggyógyítja a gerincvelő sérüléseit.