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

Award Number: K08NS096219
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = -$4,448 )
2022	2021	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/8/2022	NON-COMPETING CONTINUATION	-$4,448
														Subtotal = -$4,448

Issue Date FY: 2021 ( Subtotal = $189,401 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/3/2020	NON-COMPETING CONTINUATION	$189,401
														Subtotal = $189,401

Issue Date FY: 2020 ( Subtotal = $189,401 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/28/2019	NON-COMPETING CONTINUATION	$189,401
														Subtotal = $189,401

Issue Date FY: 2019 ( Subtotal = $189,401 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	11/28/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$189,401
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153,143
2019	2018	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/28/2018	NON-COMPETING CONTINUATION	$0
2019	2018	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	6/7/2019	NON-COMPETING CONTINUATION	-$153,143
														Subtotal = $189,401

Issue Date FY: 2018 ( Subtotal = $169,128 )
2018	2018	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/28/2017	NON-COMPETING CONTINUATION	$169,128
														Subtotal = $169,128

Issue Date FY: 2017 ( Subtotal = $169,128 )
2017	2017	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/28/2016	NEW	$169,128
														Subtotal = $169,128

Grand Total All Awards = $902,011

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

Award Number: K08NS096219

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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