NTSAD has solicited proposals for basic, translational or clinical research projects. The 2015 grants include projects related to newborn screening, gene therapy delivery methods, animal models and international patient registries.
View Press Release (.pdf)
Denis C. Lehotay, PhD, Principal Investigator
Queen's College, Kingston, Ontario
Development and validation of a rapid,
MS/MS-based method to detect
Hexosaminidase deficiency in Tay-Sachs disease
Goals of the Proposal
- Validate an existing high through-put MS/MS method for detection of reduced hexosaminidase activity (that was developed for Sandhoff disease) using dried blood spots (DBS) in normal patients and patients affected with Tay-Sachs disease (TSD).
- Determine hexosaminidase activity in 1000 de-identified DBS from normal patients and in 10-20 samples from known TSD patients to establish reference ranges and cut off values.
- Conduct a pilot-screening study using ~5000 DBS from an area of Quebec with high carrier frequency (~1/25) among French Canadians, which is similar to that found among Ashkenazi Jewish populations.
Impact of Research
Once treatment for TSD becomes available, detecting TSD by early screening, including newborn screening, and initiating early treatment will become essential to preventing the devastating consequences of this currently incurable condition. Developing, validating, and testing a rapid MS/MS based assay for measuring hexosaminidase activity in populations with a high incidence of the disease are part of the essential steps that will lead to an established newborn screen and an eventual cure.
Douglas R. Martin, PhD, Principal Investigator
Auburn University
Project: Intravascular gene therapy for
feline GM2 gangliosidosis
Goals of the Proposal
- Optimize intravascular (IV) gene therapy to treat both central nervous system (CNS) and peripheral (rest of body) manifestations of feline Sandhoff disease (SD).
- Conduct short-term (6 week) studies to compare different delivery routes (i.e. carotid artery and cephalic vein) for optimal therapeutic effect in the CNS and minimized vector levels in the periphery.
- After selecting optimal delivery route, the therapeutic effect of pretreating cats with mannitol to temporarily open the blood brain barrier and possibly permit use of a lower dose of vector for long-term therapy will be evaluated.
Impact of Research
NTSAD has previously supported efforts of the Tay-Sachs Gene Therapy Consortium to develop an effective gene therapy protocol for TSD and SD. Previous studies with direct intracranial injection of Adeno-associated virus (AAV) vectors expressing hexosaminidase dramatically increased the life span and quality of life in SD cats. While these proof-of-concept studies continue to support human application of intracranial gene therapy for TSD and SD, it is desirable to develop a less invasive and presumably safer approach that will also better address peripheral disease.
Heather A. Lau, MD, MS, Principal Investigator
Paola Leone, PhD, Co-Investigator
New York University
The Canavan Foundation, Co-funder
Project: Defining the Natural History of Canavan Disease
through Development of an International Registry
Goals of the Proposal
- Create an international electronic database to gather data prospectively in order to enhance the understanding of clinical variability, further define the relationship between genotype and phenotype, and delineate the progression of natural history of patients with Canavan disease (CD).
- Maintain a bio-repository of blood and urine specimens collected from CD patients for potential evaluation of biomarkers.
- Provide the medical community treating patients with CD with recommendations for monitoring and managing patients in order to optimize patient care.
- To define and categorize clinical endpoints that may be used for the development of clinical therapeutic trials.
Impact of Research
A disease registry is integral to elucidate the natural history of the disease and its varied clinical presentations so that appropriate clinical endpoints are obtained to show efficacy of potential therapies. These efforts will also harmonize the efforts of Dr. Annette Bley at the University Medical Center Hamburg-Eppendorf, Dr. Florian Eichler at Massachusetts General Hospital, and other clinical sites around the world to increase the power of individual studies.
The following two grants are made possible by the Katie & Allie Buryk Research Fund of NTSAD:
Florian S. Eichler, MD, Principal Investigator
Massachusetts General Hospital
Project: Registry and Repository for
Late Onset GM2 Gangliosidoses
Goals of the Proposal
- Perform a comparative review of literature reports and patient surveys for natural history data and outcome measures to establish an inventory for TSD with participation from various sources.
- Determine optimal outcome measures in LOTS patients through a prospective pilot project at MGH. Outcome measures will be judged based on variability of data, change over a 6-month period, and patient ranking of importance.
- Create and implement electronic case report forms based on outcome measures to allow several centers to participate in future trials using NeuroBANK.
- Perform prospective studies of longitudinal outcome measures and biomarkers in LOTS patients.
Impact of Research
This proposal will retrospectively and prospectively determine optimal outcome measures in LOTS patients and thereby assist in protocol development and trial design. Specifically, this proposal will identify the target population and clinical endpoints in the LOTS subpopulation of the disorder and will be vital in responding to questions of patients, families, medical practitioners, industry and regulatory bodies alike.
Eric R. Sjoberg, PhD, Principal Investigator
OrPhi Therapeutics
Project: Generation of a knock-in
mutant Hexb mouse model
Goals of the Proposal
- Create a specific missense point mutation in the beta chain of hexosaminidase that can be rescued by pharmacological chaperones, small molecules that selectively bind and stabilize certain point mutations, in order to test efficacy of chaperones that are being developed for Late Onset Tay-Sachs and Sandhoff disease.
- Compare brain levels of beta-hex, GA2, and GM2 levels in disease-causing homozygous knock-in mice to determine if a biochemical phenotype similar to Late Onset Tay-Sachs and Sandhoff diseases presents in the mouse model.
Impact of Research
Pharmacological chaperones represent a new class of treatment for patients with diseases that result from destabilization, unfolding, or misfolding of a protein. The current GM2 mouse model is a hexosaminidase knock-out (hex-/-), which does not produce any of the target protein and therefore cannot be used to evaluate various chaperones ability to bind and stabilize the protein. Creation of a knock-in mouse with a point mutation, which is equivalent to a known human late onset mutation, will allow analysis of in vivo dosing effects of specific chaperones that have already been developed. The mouse model will be made available for other late onset research.