Latest Research Developments!

In April, the NTSAD Research Initiative Committee announced 5 new grants totaling one-half million dollars for 2010. This is the largest dollar amount that has been funded in the Research Initiative’s history and is the first time that multi-year grants have been awarded: 4 of the 5 grants are two-year grants. The grants are as follows:

Jean-Pyo Lee, PhD / Evan Y. Snyder, MD, PhD (Burnham Medical Research Institute): The Therapeutic Potential of Human Induced Pluripotent Stem Cells (IPSCs) in the Sandhoff Disease Mouse Model of Lysosomal Storage Disorders.

  • Description: This cutting-edge project will investigate the mechanisms of a new type of stem cells: induced pluripotent stem (IPS) cells.
  • Benefit: If IPS derived cells could be used for therapy that would be a major step forward, as it takes away the problem of tissue rejection and the problem of working with embryonic stem cells.

Maria Traka, PhD (University of Chicago): Development of an in vitro approach to identify molecular pathways of Canavan disease

  • Description: The investigator will use a mouse model of Canavan disease to study the molecular pathways in Canavan disease.
  • Benefit: The project has a high likelihood of enhancing our knowledge of Canavan disease which will help develop therapies in the future.

Fran Platt, PhD (University of Oxford): Optimizing the Therapeutic Potential of Anti-inflammatory Therapy in Tay-Sachs and Related Diseases: Targeting IL-1ß Generated by Aberrant NLRP3 Inflammasome Activation

  • Description: Develop a mouse model of Sandhoff disease that lacks a particular receptor and use various analyses to determine the degree of anti-inflammatory benefit achieved in these mice, which will define the mechanism that triggers inflammation.
  • Benefit: This grant addresses a significant problem involving ganglioside-associated neuro-inflammation. Clinical trials could proceed quickly if confirmation of a particular inflammatory mechanism can be confirmed.

Gustavo Maegawa, PhD (Johns Hopkins University) Developing a High Throughput Screening Assay to Identify Potential Drugs for Metachromatic Leukodystrophy

  • Description: This grant is based on the principle that small molecules can enhance residual enzyme activity in patients with lysosomal storage diseases (LSD’s). Through high throughput screening, candidate compounds for metachromatic leukodystrophy will be identified.
  • Benefit: The cell-based assay will also indentify small molecules that could have broader application for treatment of other LSD’s.

Doug Martin, PhD (Auburn University): Sheep as a Model of Tay-Sachs Disease

  • Description: Characterization of disease progression in Tay-Sachs disease sheep and treatment the sheep with AAV vectors).
  • Benefit: The sheep is the first true Tay-Sachs disease animal model (as the mouse and cat models are Sandhoff disease models). Also, the large sheep brain is closer in size to the human brain. Therefore, the current proposal is an essential step to test promising therapeutic strategies.

Since its formation in the summer of 2007, the Tay-Sachs Gene Therapy (TSGT) Consortium has been diligently working toward the goal of starting a clinical trial for Tay-Sachs and Sandhoff in the next several years.

Currently the consortium is working to answer these (very simplified) questions:

  • In mice, what is the most effective combination of Tay-Sachs and/or Sandhoff genes in their natural configuration or modified to increase the enzyme production?
  • In mice and cats, which type of AAV sub-type is most effective? Based on results in the mice and cat models, the consortium expects to conclude which type is the most efficient AAV particle by mid summer 2008. If it works well in mice and cats, it is reasonable to conclude that it may also be effective in humans.

The Consortium is pleased to share these (very simplified) results:

  • It is essential to inject mice early for maximum benefit. Affected mice treated at 1 month are alive and in good health at 18 months; the humane endpoint of untreated affected mice is 4 months. The Consortium anticipates these mice will reach 24 months of age, which is the normal life span of mice. Mice treated at later stages showed some benefit but not as remarkable as the mice treated early.
  • Two treated affected cats lived to 7 and 8 months of age; normal lifespan for untreated affected cats is 4.5 months.
  • The detailed comparison of the lipids (fats) in the brains of affected mice, cats and humans is nearly complete. The Consortium is also measuring the GM2-ganglioside levels in treated affected cats, and characterizing the changes in myelin (white matter) in mice and cats.

Tay-Sachs & Sandhoff Natural History Update

Looking ahead to the clinical trial, the consortium recognized the need to accurately characterize Tay-Sachs and Sandhoff from the earliest symptoms to end-stages to determine if this (or any therapy) is having a beneficial effect. To develop this natural history, TSGT Consortium researchers, in collaboration with scientists and physicians outside the TSGT Consortium, have developed detailed questionnaires for the three forms of Tay-Sachs and Sandhoff.

The questionnaires were presented to families during the Medical & Scientific Update Session at the 30th Annual Family Conference in Tampa, FL in March 2008. The feed-back was greatly appreciated and was incorporated into the questionnaires during a meeting of clinicians at the Harvard Faculty Club on April 17th.

We need your help to make the natural history study as accurate and complete as possible. If you are not currently a member of the PSG of NTSAD and you have or had a loved one affected by Tay-Sachs or Sandhoff, please contact Kim Crawford, Director of Member Services at Kim@ntsad.org or 800-906-8723 to be part of the study. Please note that participation is completely voluntary and will not directly benefit you or your loved one.