# Global AAV gene therapy of Tay-Sachs disease in sheep.

> **NIH NIH K08** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $189,401

## Abstract

PROJECT SUMMARY
Lysosomal storage diseases (LSDs) consist of >40 distinct disorders, with a cumulative prevalence of 1 in
7,700 live births, similar in frequency to cystic fibrosis and hemophilia. Each LSD has an underlying defect in
lysosomal function that leads to widespread storage of undegraded substrates in all tissues. Many lysosomal
storage diseases have some level of neurologic involvement, with several previously thought peripheral tissue
only subtypes now categorized as neuropathic. Though effective treatments have been developed for
peripheral manifestations of some lysosomal diseases, those with neurological components have been virtually
untreatable. Tay-Sachs (TSD) and Sandhoff disease (SD) are each caused by a subunit deficiency in the
enzyme Hexosaminidase (Hex), and are almost clinically indistinguishable. Intracranial injection of adeno
associated viral (AAV) vectors has led to > 4-fold increases in life span and vastly improved quality of life in
mice and cats with Sandhoff disease. The newly discovered Tay-Sachs sheep is the only relevant animal
model of Tay-Sachs disease (TSD) and may inform on challenges associated with TSD not experienced in the
Sandhoff cat and mouse. Additionally, testing therapy in an authentic model of TSD with brain and body size
on the same order of magnitude as children, will provide invaluable data on vector safety, biodistribution and
efficacy. Sheep with Tay-Sachs experience heterogeneous clinical signs which are representative of the highly
variable age of onset and clinical signs experienced by human juvenile patients. The first aim of this proposal is
to identify, characterize and validate biomarkers of sheep Tay-Sachs and understand their relationship to
disease progression. This project will make use of ultra-high field (7 Tesla) magnetic resonance imaging,
combined functional MRI–electroencephalography, MR spectroscopy, diffusion tensor imaging as well as
metabolomics and electrodiagnostic testing; and these techniques will be used to evaluate therapeutic success
in Aim 2. Preliminary studies have shown that simultaneous delivery of both Hex subunits is ideal for normal
ratios of Hex isozymes, but enzymatic levels were below normal. Therefore, we plan to test a novel bicistronic
vector that expresses both Hex subunits in a single construct with superior enzymatic expression using a novel
AAV capsid that transduces the brain with greater efficiency than the industry standard AAV9 (Aim 2). To
bypass the invasiveness of parenchymal brain injections, we will administer this new AAV by intravenous
injection and compare side by side with the “the gold standard” routes of Thalamic+CSF delivery. Conclusions
from this project will ultimately inform future human clinical trials for GM2 gangliosidosis as well as other AAV
trials for LSDs.

## Key facts

- **NIH application ID:** 9829587
- **Project number:** 5K08NS096219-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Heather L Gray-Edwards
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $189,401
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829587

## Citation

> US National Institutes of Health, RePORTER application 9829587, Global AAV gene therapy of Tay-Sachs disease in sheep. (5K08NS096219-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9829587. Licensed CC0.

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