To develop a safe and effective state of the art gene-based treatment for the Tay-Sachs and Sandhoff diseases (subtypes of GM2 gangliosidosis)
Summary and Achievements
Tay-Sachs Disease (TSD) is an inherited neurological disease that severely affects the nervous system, and causes premature death. Children with the most common and severe form of Tay-Sachs Disease develop normally for the first months of life, but slowly deteriorate until death, usually by age 5. Juvenile and Late Onset forms are also devastating conditions. Although TSD was first described in the 1880's, there is currently no treatment for these GM2 Gangliosidosis diseases, a subset of a group of lysosomal storage diseases (LSDs). They are fatal in children and progressively disabling in their adult onset forms.
In recent years, outstanding therapeutic results have been achieved in mouse models of TSD using state-of-the-art gene therapy systems known as adeno-associated viral (AAV) vectors. Translation of these findings from mice to humans is a significant challenge that requires a considerable amount of research.
The Tay-Sachs Gene Therapy Consortium was founded in 2007 to develop a safe and effective gene-based treatment for the closely related Tay-Sachs and Sandhoff diseases (subtypes of GM2 gangliosidosis). The Consortium consists of scientists from an international coalition of institutions, including University of Massachusetts Medical School, New York University, Harvard University, Cambridge University, Boston College and Auburn University. Since its inception, the Consortium has striven to perform the preclinical safety and efficacy studies needed for the first-in-human clinical trial of gene therapy for Tay-Sachs and Sandhoff diseases. Some significant milestones achieved by the Consortium are listed below:
- Defined the natural history of GM2 gangliosidosis as a baseline to assess outcomes in clinical trials
- Demonstrated proof-of-principle that gene therapy is safe and effective in mice affected with GM2 gangliosidosis
- Showed that GM2 cats treated by gene therapy have dramatic improvements in quality-of-life and live >4 times longer than untreated cats.
- Gene therapy studies in Tay-Sachs sheep have demonstrated that the same therapeutic principle of infusing AAV vector into the thalamus is effective to achieve widespread distribution of hexosaminidase in a large brain. These important results indicate that it is highly likely the same will be possible in the larger human brain.
- Refined vector design and delivery routes to the brain to optimize gene therapy
- Performed safety studies in normal mice and non-human primates (ongoing)
- Received $3.6 million from the National Institutes of Health to develop the AAV gene therapy for Tay-Sachs and Sandhoff diseases
- Received grants from the National Tay-Sachs and Allied Diseases and Cure Tay-Sachs foundations and others to perform supportive studies in large animals, preliminary toxicology, feasibility of manufacturing process.
- Held pre-pre-IND (investigational new drug) teleconference with the U.S. Food & Drug Administration (FDA).
- Submitted pre-IND document and held teleconference with FDA.
- FDA has provided further guidance in the design of IND-enabling toxicity and biodistribution studies necessary for submission of IND.
- Consortium now is performing final preclinical safety and efficacy studies needed for FDA approval of the first clinical trial. Work is also going on on preparation of the first manufacturing lot of compound needed for clinical studies and final documentations to send for FDA submission. It is planned to initiate clinical studies in the beginning of 2017.
- Work of consortium was highly regarded and consortium members published 14 articles in peer-reviewed journals as well as 2 book chapters and presented the work in international meetings.
- The TSGT consortium has maintained a close relation with the patient community through participation in the annual NTSAD family meeting and release of status updates. This close interaction with the community and foundations has been critical to continue the project through funding efforts and support. Moreover we anticipate the knowledge the community has gained over the years about the project will play a crucial role in the clinical trial as we anticipate extensive help in recruiting patients through the foundations and patient community.
It is expected that clinical studies in Tay-sachs patients would stop disease progression in children and adults with Tay-Sachs disease. This study would help to develop similar treatment for other genetic neurological diseases.