Osiris Therapeutics inc said on Thursday that Canadian health regulators have approved its treatment for acute graft-versus host disease in children, making it the first stem cell drug to be approved for a systemic disease anywhere in the world.

Osiris shares rose 14 percent to $6.00 in extended trading after the news was announced.

Graft versus host disease (GvHD) is a potentially deadly complication from a bone marrow transplant, when newly implanted cells attack the patient’s body. Symptoms range from abdominal pain and skin rash to hair loss, hepatitis, lung and digestive tract disorders, jaundice and vomiting.

The disease kills up to 80 percent of children affected, Osiris said. To date there have been no approved treatments for the disease. Canadian authorities approved the therapy, Prochymal, for use in children who have failed to respond to steroids.

Prochymal was approved with the condition that Osiris carry out further testing after it reaches the market. C. Randal Mills, the company’s chief executive, said in an interview that could take three to four years.

Some investment analysts have been skeptical about Prochymal’s future. in 2009, two late-stage clinical trials failed to show the drug was more effective overall than a placebo in treating the disease, though it showed promise in certain subgroups of patients.

Since then, the company has mined data from all its clinical trials to show that in patients with severe refractory acute GvHD — those who have more or less failed all other therapies — Prochymal demonstrated a clinically meaningful response at 28 days after therapy began in 61-64 percent of patients.

In addition, treatment with Prochymal resulted in a statistically significant improvement in survival when compared with a historical control population of pediatric patients with refractory GvHD.

The Canadian authorities approved the drug on the basis of that data, the company said.

FDA submission this year

Osiris, which is based in Columbia, Maryland, plans to apply for marketing authorization with the U.S. Food and Drug Administration by the end of this year, including the newly-analyzed information. Mills said that if the FDA were to approve the drug, he would expect it to be on similarly conditional terms as outlined by the Canadian authorities.

In general, the FDA does not approve drugs based on subset analyses.

Prochymal is made up of bone marrow stem cells derived from an adult donor and is designed to control inflammation, promote tissue regeneration and prevent scar formation. It is not entirely clear how it works to help patients with GvHD, of which there are between 3,500 to 4,000 worldwide, Mills said.

Osiris said it will receive at least eight years of exclusivity in the Canadian market. but competition is heating up elsewhere.

Athersys inc said last month it had met with the FDA to discuss the results of a recently completed clinical trial of its MultiStem stem cell treatment to prevent GvHD in patients being treated for leukemia or other conditions that place them at risk of the complication.

Dozens of adult stem cell therapies are moving through clinical trials, and Canada’s approval of Osiris’s drug will likely boost optimism in the sector. Stem cells derived from adult tissue such as fat or bone marrow circumvent the ethical concerns raised by the use of cells derived from embryos.

In 2008, Genzyme Corp, which is now owned by Sanofi SA, paid $130 million to Osiris and agreed to pay up to $1.25 billion more if Prochymal and another Osiris drug, Chondrogen, designed to repair tissue in damaged knees, reached the market and achieved certain sales levels.

In February, Sanofi said it had discontinued its project with Prochymal. Osiris said the statement was issued without its consultation and that it had not received notice from Sanofi regarding the discontinuation. however, the company said that the agreement between the two companies provides that in this instance all rights to Prochymal revert to Osiris without compensation to Sanofi.

Scientists have long recognized Duchenne muscular dystrophy (DMD) is due to dystrophin gene mutations caused by a single a devastating disease. Dystrophin protein in the maintenance of muscle integrity play a crucial role; when the body’s lack of Dystrophin, the muscles are extremely vulnerable. recently, however, researchers from Stanford University published in the journal Cell, said no longer play when the skeletal muscle stem cells repair function, disease symptoms will appear. So that in essence Duchenne muscular dystrophy may be a stem cell disease.

"This shows that the Duchenne muscular dystrophy and dystrophin deficiency is not just a single-gene genetic diseases, it is a stem cell disease," study leader, Helen Blau of Stanford University School of Medicine, said: "This means that to be successful treatment of the disease can not just target muscle fiber, may also need to target muscle stem cells. "

"The new discovery researchers find treatment for the disease and the most appropriate treatment time is of great significance," the paper’s corresponding author, University of California at San Francisco’s Jason Pomerantz, said: "it indicates that only the use of muscles or enhance muscle function treatment, while ignoring the role of stem cells will likely lead to failure, and may even accelerate the disease progression. This is like gasoline in the tank is no longer the case, no matter how hard to step on the gas pedal is useless. "

"in addition to this discovery has opened a mystery over the past 25 years, the genetic defect in mice show only mild or asymptomatic performance reasons. The existence of the phenomenon has never been the researchers used a mouse modelDuchenne muscular dystrophy to carry out the pathophysiology of or related therapy. "Blau said:" in addition it may also be that the mice are smaller and life expectancy is not long enough, therefore not suitable for resolution of the disease. This concept has been continued to the present. "

In the new study, researchers showed that mice and humans because the chromosomes characteristic of the two species led to the differences between the symptoms of the disease. The top of mouse chromosome telomere repeat DNA region is also known as longer relative to humans. Blau and her team found that mutation of dystrophin gene with shortened telomeres in mice, and often show a more severe disease symptoms and with age deteriorating condition, just as the performance of human patients.

Telomeres in the cell is mainly to protect the role of chromosomes, telomere length gradually shortened with cell division. When it reduced to a certain length, you can start the intracellular events leading to cell death. Study found that longer telomeres in mice muscle stem cells have a more lasting effect and greater ability to repair defects caused by the dystrophin muscle damage.

"Mice with short telomeres were shown all the features of this disease," Blau said: "these animals can not treadmill running, their power was weakened, and their thin diaphragm. And in the muscle weakness also accompanied by a decline in muscle stem cell regeneration. "

"Dystrophin leads to muscle loss sustained damage. And when stem cell depletion, the symptoms will appear. these mice caught in a vicious cycle that damage, repair, and then damage, then repair until the repair capacity is exhausted. And those who side short grain sooner run out of mice’s ability to repair them, "Pomerantz said.

When the researchers isolated muscle stem cells transplanted into healthy mice sick, the disease symptoms appeared to reduce the signs.

"This is the first time in mice as a model system to study the disease. a new type of mouse model of physiological changes in the study of disease pathology in our way," the first authors Foteini Mourkioti said: "Now we know that muscle stem cells are the Duchenne muscular dystrophy important factor. and we have begun to consider using some of the more accurate method to treat this disease. just treatment of muscle repair may only play a role in the short term, do not even play a role. in fact , it will quickly run out of muscle stem cells to cause disease worse. Timing is a critical factor. " "The strategy for treatment of DMD patients should be in the first years of life on them for early intervention treatment, and this organization has emerged compared to late treatment failure, no doubt there will come a better therapeutic effect," first author of the article, Sanford-Burnham Medical Research Institute of Alessandra Sacco said.

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Cell  DOI: 10.1016/j.cell.2010.11.039

Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice

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Alessandra Sacco1, 4, 5, Foteini Mourkioti1, 4, Rose Tran1, Jinkuk Choi2, Michael Llewellyn3, Peggy Kraft1, Marina Shkreli2, Scott Delp3, Jason H. Pomerantz1, 6, , , Steven E. Artandi2 and Helen M. Blau1, ,

1 Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA

2 Department of Medicine, Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA

3 BioX Program, James H. Clark Center for Biomedical Engineering and Science, Stanford University, CA 94305, USA

Received 18 may 2010;  revised 18 September 2010;  accepted 2 November 2010.  Published online: December 9, 2010.  available online 9 December 2010.

In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. we postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdxphenotype results from greater MuSC reserve fueled by longer telomeres. we report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. these data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.

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Tags: DMD, dystrophin, mTR, Stem Cells