Leading the worldwide fight to treat and cure
Tay-Sachs, Canavan, GM1 and Sandhoff diseases

2010 Research Initiative Grants

Jean-Pyo Lee, PhD / Evan Y. Snyder, MD, PhD
Tulane University

The Therapeutic Potential of Human Induced
Pluripotent Stem Cells (IPSCs) in the Sandhoff
Disease Mouse Model of Lysosomal Storage Disorders


Researchers investigated the therapeutic potential of human-induced pluripotent stem cells (IPSCs) for Tay-Sachs related Sandhoff Disease (SD) in a mouse model. It was found that when combined with a protein factor called SDF, the transplanted cells could migrate to the damaged areas, delay the onset of motor dysfunction, and extend the life span of SD mice.


The basis of Sandhoff disease is a deficiency in two enzymes called Hex A and Hex B. Using transplanted stem cells to deliver normal enzymes represented a unique approach to correct the imbalanced metabolic system in the patient. The pilot study using animal SD models overcame the drug targeting issue by protein activation and demonstrated considerable therapeutic benefits of stem cell therapy. The data and results from this work advanced the development of stem cell therapy in future clinical trials.

Future work:

A few directions of follow-up study will be pursued. First, researchers will explore alternative ways to enhance the migration capacity of implanted cells. In addition, stem cells induced from both Sandhoff Disease human and mouse skin cells were studied to evaluate species and immune compatibility. At last, gene therapy to induce correct gene expression will be tested as combination therapy.

Gustavo Maegawa, PhD
Johns Hopkins University

Developing a High Throughput Screening Assay to
Identify Potential Drugs for Metachromatic Leukodystrophy 


With the project funded by NTSAD, researchers developed expertise to convert skin cells into brain cells, called “induced neuronal cells”. The skin cells were taken from Metachromatic leukodystrophy (MLD) patients. The induced-neuron cells would be used as model system in the future work to test potential drug candidates for MLD and other neurological diseases.


Metachromatic leukodystrophy (MLD) is one of the lysosomal diseases and is caused by the deficiency of an enzyme in the lysosomes called arylsulfatase A.

MLD is associated with severe and progressive neurological problems such as seizures, coordination and cognitive problems, muscle weakness and atrophy. Unfortunately, the current therapies available for MLD poorly focus on treating brain symptoms.

Previous work from Maegawa lab [1] identified chemical compounds that were able to bind the defected enzymes in MLD patients, rendering them more stable and preventing them from early degradation. These compounds had the potential to rescue the misfolded enzymes in some cases of MLD. And the potency and efficacy of the compounds needed further testing in relevant biological systems, such as diseased cells, tissues, and animal models. This project enabled such testing in the induced-neuron cells that mimic neuron cells from patients.

Future work:

The skin-derived brain cells would be used to test the chemical compounds that may be able to rescue the enzyme deficiency in MLD. The novel technologies of cell conversion could be applied to other lysosomal diseases, especially those that are associated with neurological problems.

Link to resulting publication in PubMed.gov: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244463/

[1] Geng H, Whiteley G, Ribbens J, Zheng W, Southall N, Hu X, Marugan JJ, Ferrer M, Maegawa GHB. Novel Patient Cell-Based HTS Assay for Identification of Small Molecules for a Lysosomal Storage Disease. PLoS One. 2011; 6(12):e29504.

Doug Martin, PhD
Auburn University

Sheep as a Model of Tay-Sachs Disease
(Tay-Sachs Gene Therapy Consortium)

The Tay-Sachs disease course was charted in the newly described sheep model. Gene therapy was tested in the animal, with the clinical outcomes and safety profile measured.


The research took advantage of the sheep model of Tay-Sachs disease and studied the effect of gene therapy on the disease progression.

Life span of the treated sheep increased to an average of 14.4 months (~60% increase over untreated). Gene therapy also improved quality of life by delaying the onset of certain disease symptoms such as ataxia. Biophysical imaging MRI confirmed the safety and tolerance of the therapy in the sheep.


The sheep is the first true Tay-Sachs (HexA deficiency) disease animal model, because the current mouse and cat models are Sandhoff disease (HexA and HexB deficiency) models. The larger sheep brain is closer in size to the human brain, which allows more detailed biophysical imaging such as MRI. Therefore, the proposal is an essential step to test promising therapeutic strategies before clinical trials.

Future Work:

Future priorities for the sheep gene therapy include:

  1. Move the sheep flock from current location to the research facility, as required by National Institutes of Healthcare in a grant;
  2. Continue to investigate and develop ways of therapy administration to ensure broad distribution of enzyme in the brain and spinal cord; and 
  3. Further refinement of the gene therapy system in order to achieve beneficial outcomes at lower doses.

Fran Platt, PhD
University of Oxford

Optimizing the Therapeutic Potential of
Anti-inflammatory Therapy in Tay-Sachs and
Related Diseases: Targeting IL-β Generated
by Aberrant NLRP3 Inflammasome Activation


Researchers investigated the contribution of a pro-inflammatory cytokine to Sandhoff disease in mouse models and confirmed the hypothesis that cytokines promote pathogenesis.


Inflammation is a common feature of lysosomal storage diseases, including Sandhoff and Tay-Sachs disease and actively contributes to disease progression. It was yet unclear whether targeting inflammation would be of therapeutic benefit to patients.

Previously, the level of a pro-inflammatory molecule (cytokine) was found to be significantly higher in the mouse model of Sandhoff disease (hexb-/- mouse) compared to healthy mice and the mechanism that controlled the cytokine production was abnormal [1].

Life span and behavior studies demonstrated that the absence of the cytokine improved the disease symptoms of the Sandhoff mice. The findings from this work indicated the therapeutic potential of anti-inflammatory therapy in treating Tay-Sachs, Sandhoff, and related diseases. And confirmation of IL-1β contribution to disease will allow rapid transfer of clinical testing of existing validated drugs (e.g. IL-1R antagonists).

Future work:

As a result of the neurological benefit of genetically deleting IL-1β activity in mice, the scientists have initiated the trial of an IL-1R antagonist that crosses the blood-brain barrier in Sandhoff disease mice, which could be prelude to a clinical trial in Tay-Sachs and Sandhoff disease patients.

[1] Jeyakumar, M., Thomas, R., Elliot-Smith, E., Smith, D.A., van der Spoel, A.C., d’Azzo, A., Perry, V.H., Butters, T.B., Dwek, R.A. and Platt, F.M. (2003). Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126, 974-987.

Maria Traka, PhD
University of Chicago

Development of an in vitro approach to identify
molecular pathways of Canavan disease


Using a special type of neuron cells, oligodendrocytes, cultured from the Canavan mouse model, the researchers investigated the pathological mechanism of Canavan disease at a molecular level. It was found that the loss of key enzyme ASPA function did not lead to the cell death or disease related functional defects of oligodendrocytes, indicating a role of ASPA outside of myelination.


Canavan disease is a rare white matter leukodystrophy that features with myelin sheath degeneration and neurological impairment. The underlying cause of Canavan disease is known to be the mutations of the aspartoacylase gene (ASPA). ASPA is highly expressed in oligodendrocytes after birth, especially during the formation of the myelin sheath around the axons (myelination). It was hypothesized that the loss of enzyme activity in oligodendrocytes led to the defects of myelination and thereafter loss of neurons. However, the detailed molecular mechanism remained unclear. Traka and researchers in the lab carried out a set of cell based experiments to investigate the correlation. From the study, no direct association was found between functional activity of ASPA and the myelination of oligodendrocytes, indicating a more profound and complicated disease mechanism beyond oligodendrocytes.

Future work:

A number of genes, which may play a role in the Canavan disease pathogenesis, were identified from this work. As a next step, researchers will evaluate the importance of these genes in Canavan disease using a myelinating cell culture system. The study could help identify novel molecular pathways and potential therapeutic targets for Canavan disease.