NTSAD Research Initiative
2007 Moving Toward a Cure
“Is there a cure?” Inevitably this is the first question a family asks when they contact NTSAD. Today, we can say we are getting closer and hope is on the horizon. Together with other funders, NTSAD’s Research Initiative has distributed close to $1 million in seed grants to help researchers elevate their work to meet the competitive standards of the National Institute of Health (NIH). In fact, several grantees have progressed to receiving, collectively, over $2 million in funding from NIH.
The research funded by NTSAD holds great potential and hope for families living with these diseases and those yet to be diagnosed. The work being done now, as a result of NTSAD funding, is solving the puzzle on how to conquer these diseases through gene therapy, the blood-brain barrier and stem cell treatment.
2007 was truly an exciting year for development of potential therapies for leukodystrophies and lysosomal storage diseases. Here is a brief summary of those achievements.
- In February, the NTSAD Research Initiative matched the funds raised by several NTSAD Canavan families to award a grant to Aryan Namboodiri, PhD research project Preclinical Research toward Acetate Supplementation Therapy for Canavan Disease. The central theory of this project is that Canavan disease results in defective myelin because of a lack of acetate derived from N-acetylaspartate. This therapeutic approach would simply provide missing acetate in the form of an oral supplement. Mouse model results have been very promising. A primary goal of this project is to collect the necessary preclinical data to move forward to Phase I clinical trial in children.
- Simplified: Acetate supplement therapy for Canavan disease could be a simple and inexpensive therapeutic approach administered orally in a supplemented infant formula.
- Simplified: Acetate supplement therapy for Canavan disease could be a simple and inexpensive therapeutic approach administered orally in a supplemented infant formula.
- Last month Zymenex, a Danish biotech company, launched Phase II clinical trials of Metazym, an enzyme replacement therapy for Metachromatic Leukodystrophy (MLD). At this time the trials are only in Europe and any U.S. patients interested would need to relocate to Europe for 12 – 52 weeks. The Metachromatic Leukodystrophy Foundation is working closely with Zymenex to find a way to include U.S. patients in the trial but the substantial financial increase of adding a trial site in the U.S. continues to be the biggest obstacle.
- Update: April 24, 2008 -- Shire Acquires Metazym from Zymenex Shire HGT has acquired Metazym from Zymenex for $135M. Shire will continue to expedite the testing and market release of Metazym.
Metazym is a promising enzyme replacement therapy (ERT) for MLD.
This is exciting for MLD affected families. Shire can and will likely apply significant corporate resources to these later stage tests and an expedited market release. In addition, this external endorsement of Metazyme seems to validate the effectiveness of this ERT in advance of seeing published Phase II European clinical trial results.
Metazym is nearing completion of Phase II clinical trials in Europe. An IND has been granted by the FDA to prepare for Phase II clinical trials in the US. In addition, Orphan Drug Status has been granted in both Europe and the US for Metazym.
- Update: April 24, 2008 -- Shire Acquires Metazym from Zymenex Shire HGT has acquired Metazym from Zymenex for $135M. Shire will continue to expedite the testing and market release of Metazym.
Metazym is a promising enzyme replacement therapy (ERT) for MLD.
- Researchers published the 3-dimensional shape of aspartoacylase, the enzyme deficiency which causes Canavan disease, in the January issue of Proceedings of the National Academy of Sciences of the USA. Enzymes fold into specific 3-D shapes which provide the enzyme with its functionality. Understanding the correct shape and function of aspartoacylase provides clues to how to make the enzyme work properly in children affected by Canavan disease.
- Researchers at the University of Minnesota published a paper in Nature Bone Marrow Transplantation demonstrating that N-acetly-L-cysteine (NAC) increases the chance of success bone marrow transplantation (BMT) in advanced Adrenoleukodystrophy. With this new insight into BMT the physicians at the U of MN felt it was time to try the new protocol in other allied diseases. Krystie Karl-Steiger is 17 months old and affected by Tay-Sachs. Krystie is currently 37 days post transplant and doing relatively well. Follow her progress at http://www.caringbridge.com/visit/krystie.
- Simplified: After success with a less toxic protocol for bone marrow transplant in Adrenoleukodystrophy cases, it is now being tried in an Infantile Tay-Sachs case.
- Simplified: After success with a less toxic protocol for bone marrow transplant in Adrenoleukodystrophy cases, it is now being tried in an Infantile Tay-Sachs case.
- In March a breakthrough paper was published in Nature Medicine on the multiple mechanisms which stem cells act to benefit mice with Sandhoff disease. This paper was the result of an international collaboration led by Evan Snyder, MD, PhD, and spearheaded by a member of his lab, Jean-Pyo Lee, P.D, of the Burnham Institute for Medical Research (“Burnham”). This study yielded many scientific firsts, including the first successful use of human embryonic stem cells (hESCs) in degenerative disease, significantly preserving function and prolonging life in the Sandhoff mouse model and laying the ground work for a potential clinical trial, first use of hESCs grown in a manner suitable for clinical use, and the first head-to-head comparison of human embryonic and ‘adult’ stem cells in the same disease model using the same metrics in the hands of the same investigators – just to name a few of the first breakthroughs in this paper! The NTSAD Research Initiative is proud to be acknowledged as a supporter of this important work.
- Simplified: Stem cell therapy significantly prolonged life and increased functioning level in mice with Sandhoff disease. It also demonstrated that the therapeutic effects of stem cells act through several different ways.
- Simplified: Stem cell therapy significantly prolonged life and increased functioning level in mice with Sandhoff disease. It also demonstrated that the therapeutic effects of stem cells act through several different ways.
- The past year also brought about in a trans-Atlantic collaboration of a group of dedicated scientists determined to bring gene therapy for Tay-Sachs and Sandhoff to clinical trial in the next three – five years, a very ambitious goal. NTSAD is honored to be valued member of this collaboration and will continue to promote the interests of our membership and all those affected by these diseases. Two Research Initiative Grants was awarded to two very promising researchers who are key members of this group effort.
- Simplified: Successful research comes from collaborations!
- Simplified: Successful research comes from collaborations!
- In April ExSAR Corporation announced that the FDA approved Phase I clinical trials of EX-101 for the potential treatment of Late Onset Tay-Sachs and Sandhoff. EX-101 is a small molecule pharmacological chaperone for Hex-A. Pharmacological chaperones stabilize normal and misfolded (mutant) enzymes and promote trafficking from the endoplasmic reticulum to the target organelle – in this case the lysosome, where Hex A breaks down gangliosides, the fatty substance that accumulates. EX-101 is administered orally and has shown remarkable efficacy in cell-based models of Late Onset Tay-Sachs and Sandhoff. It is already FDA approved for other indications. NTSAD is in close contact with trial sites and will be contacting potential trial participants directly in the near future.
- Simplified: A molecular chaperone increases enzyme activity by binding to the misfolded enzyme and help it fold into the correct shape. EX-101 is believed to have this effect on the Hex-A enzyme.