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

2011 Research Initiative Grants

Florian Eichler, MD
Massachusetts General Hospital

Clinical Outcome Measures for a Gene
Therapy Trial in Infantile and Juvenile GM2


Researchers performed prospective neurological and neuropsychological evaluations in children with GM2 and developed a MRI Severity Scale for patients with GM2. Both of these efforts are helping scientists in clinical trial design for gene therapy in GM2, as they help consolidate outcome measures and endpoints for the trial.


The clinical studies showed that adaptive skills in GM2 were significantly affected by neurological decline. Documentation of the finding would be important as outcome measure in future trials. The imaging studies demonstrated remarkable consistency in characteristic features, with infantile and adult forms of the disease displaying the most specific abnormalities captured by the scoring system. Applying the scoring method, it was found that the number of brain MR abnormalities was higher in younger than older subtypes of GM2. Infantile patients carried the largest disease burden in gray and white matter structures. Adults, on the other hand, displayed severe cerebellar atrophy. These imaging parameters allowed a first gross grading system of brain abnormalities that would in future allow implementing more advanced imaging modalities.

Further longitudinal studies will be conducted in the patient population by video and telephone interviews. In addition, clinical correlations will be performed for the imaging scoring system. This study would allow a first structure-function correlation in patients with GM2.

Link of resulting publication in PubMed.gov: https://www.ncbi.nlm.nih.gov/pubmed/22025593


Guangping Gao, PhD
University of Massachusetts Medical School

Optimization of Efficacious Gene
Therapy for Canavan Disease


Gao studied the efficiency of gene therapy delivery to the Central Nervous System (CNS) of mouse models by intravenous (IV) and intracerebroventricular (ICV) injections and found that the treatment was able to rescue the lethal phenotype and improve motor functions of the animals.


Canavan disease, as a debilitating genetic disorder, has currently no cure or appropriate treatment. Gene therapy bears tremendous promise to correct the disease from the roots of the issues. Different strategies using non-viral and viral formulations have been attempted, yielding varying degrees of improvement in disease symptoms. However, none of the past studies had been able to produce enduring benefits for Canavan patients. One of the issues was that not enough copies of gene were successfully delivered and incorporated at the target location in the patients’ brain.

Researchers in Gao lab engineered new virus vectors with improved gene transducing efficiency at CNS. And the vectors were tested on mouse model via two different delivery routes: systematic IV injection and direct-to-brain ICV injection. The survival rates of the animals were significantly improved in both experiments, indicating the success in vector engineering. However, the systematic IV injection results in better improvement of the motor functions of the animals than direct-to-brain injection, indicating the pathology of Canavan disease is not limited in the CNS, but the peripheral organs like kidneys, eyes, and muscles are also involved.

Link of resulting publication in PubMed.gov: https://www.ncbi.nlm.nih.gov/pubmed/23817205


Yu-Tah Li, PhD
Tulane University

Studies of Taurine-Conjugated GM2
in Tay - Sachs Disease


This study set out to explore the function and significance of a special group of lipids glycosphingolipids (GSLs) in the brain Tay-Sachs (TS) patients. Qualitative and quantitative biochemical assays were applied to measure and profile this group of lipids at different locations of TS brain.


Before this study, an unusual and novel GM2 derivative, taurine-conjugated GM2 (TGM2), was found in TS brains but not in normal brains [1]. A sensitive and convenient assay was needed to detect the quantity of TGM2 in potential mechanism studies. This pilot work explored antibody-based and mass-spectrometry based assays to detect TGM2 in different TS brain samples. However, the quantity of lipid was below the detection limit of both samples so further sample enrichment was needed for the assays.

Proteomic analysis demonstrated different lipid composition in the glycosphingolipids (GSLs).

[1] Li, Y.-T., Maskos, K., Chou, C.-W., Cole, R. B., Li, S.-C. (2003) Presence of an unusual GM2 derivative, taurine-conjugated GM2 in Tay-Sachs brain. J. Biol. Chem. 278: 35285-35291.

Fran Platt, PhD
University of Oxford

Validation of a Potential Biomarker for
the GM1 and GM2 Gangliosidoses


The study set out to evaluate a special type of red blood cell as novel potential cellular biomarker in GM1, GM2, and Sandhoff diseases. No clear correlation was found between the amount of echinocytes and the progression/severity of disease from human patient samples.


A biomarker is a measurable marker of disease severity and progression. It serves as critical tool in investigating disease mechanism and in conducting clinical trials for experimental therapies. As of the completion of this study, there were no validated biomarkers for GM1, GM2, and Sandhoff Diseases. The study tested the hypothesis on cellular biomarker and information gained advanced the knowledge of the scientific and clinical community.

Link of resulting publication in PubMed.gov: https://www.ncbi.nlm.nih.gov/pubmed/25284324