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

2016 Research Initiative Grants

Martin Grootveld, PhD
Leicester School of Pharmacy
De Montfort University, UK

Co-Principal Investigator: Cynthia Tifft, MD, PhD

Rapid Identification of New Biomarkers
for the Classification of GM1 and GM2
Gangliosidoses: A HNMR-linked
Metabolomics Strategy

The objective of this study is to identify biomarkers of GM1 and GM2 in plasma, CSF (cerebrospinal fluid), and/or urine that have been sampled repeatedly from affected individuals over time. This will contribute to an overall goal of a greater understanding of disease pathogenesis as well as identification of potential drug targets.

The study will use nuclear magnetic resonance (NMR)-linked metabolomics to screen for biomarkers in samples from GM1 and GM2 patients and used advanced multidimensional datasets to extract detailed
information. The study will further identify and validate potential NMR targets by liquid chromatography-mass spectrometry (LC-MS), a technique that has a higher level of sensitivity

Angela Gritti, PhD
San Raffaele Scientific Institute
San Raffaele Telethon Institute for Gene Therapy (Italy)

Novel combined gene/cell therapy
strategies to provide full rescue of the
Sandhoff pathological phenotype

This study will evaluate gene and cell therapy approaches in the mouse model of Sandhoff disease. 

Specifically, this study will compare three therapeutic

1) direct intracranial lentiviral gene therapy,

2) neural stem cell transplantation (with or without gene
correction of cells)

3) and bone marrow transplantation.

These therapies will initially be tested individually and subsequently in combination. A combination of these therapies has demonstrated a synergistic effect and extension of lifespan in a mouse model of a similar disease providing the rationale to assess these therapies for Sandhoff and Tay-Sachs diseases.

Cynthia Tifft, MD, PhD
National Human Genome Research Institute
National Institutes of Health

Clinically Relevant Outcome Measures
for Patients with Late Onset Tay-Sachs
disease Ascertained Real-Time Through
Patient Wearable Technology

Funded by Katie & Allie Buryk Research Fund of NTSAD

This study is a next step in identifying relevant outcome measures for clinical trials. This six month exploratory study will use 5-8 ambulatory or partially ambulatory adult patients with late onset Tay-Sachs or Sandhoff disease to collect patient data on ambulation, falls, wake/sleep cycles, and other patient input that can be tested as potential clinically relevant outcome measures for future clinical trials. Data is collected through a wearable device and transmitted through a mobile app to Dr. Tifft for analysis. The data collected will be compared to clinical testing including gait lab metrics to be conducted at the NIH Clinical Center at the time of initial evaluation and at the six month endpoint.

Beverly Davidson, PhD
Children's Hospital of Philadelphia

Fran Platt, PhD
Oxford University (UK)

Identifying Novel Therapeutics for
Treating GM2 Gangliosidoses

Co-funded with the Katie & Allie Buryk Research Fund and the Vera Pesotchinsky Research Fund of NTSAD

Substrate reduction therapy (SRT) has the potential to be broadly applicable to several lysosomal storage diseases, including the gangliosidoses. However, the SRT drug Miglustat (approved for Gaucher disease in 2002) does not cross the blood-brain barrier to an extent that could mediate benefit in patients with Tay-Sachs disease.

This study will analyze Miglustat and the closely related drug Lucerastat using human macrophages (a type of white blood cell that digests cellular debris and foreign objects). This comparison will allow identification of common pathways affected by both Miglustat and Lucerastat and determination of other drugs that act in a similar manner. Drugs that share common features, but have improved central nervous system penetrance for treating the gangliosidoses (including GM-1), will then be tested for their ability to reduce stored substrate levels when applied to patient-derived cells. As Miglustat has
additional anti-inflammatory properties relative to Lucerastat, this analysis may also shed light on the inflammatory pathways targeted by Miglustat.