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Alternative delivery of adeno-associated virus therapeutic vector for the treatment of neuromuscular disorders

Award Number: R01AR073908
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Gene therapy using Adeno-associated viral vectors (AAVs) is a very promising tool for treatment of many mus- culoskeletal disorders. Multiple strategies are currently in clinical trials using either intramuscular (IM) or intra- vascular (IV) delivery of the vector. Despite promising initial results, the effect is only local for IM treatment or requires a large amount of virus for IV delivery since the dose is calculated per kilogram body weight. While suitable for small children, AAV therapies become more problematic for the treatment of teenagers or adults due to high vector production costs as well as potential safety concerns at very high doses. In addition, many muscular disorders also display pathology of the nervous system (NS). Therefore, efficient simultaneous tar- geting of both the muscle and NS would likely enhance therapeutic outcomes. In this project, our objective is to test the efficiency of delivering the gene therapy vectors through cerebral spinal fluid (CSF) instead of IV injec- tions in order to target both muscle and nervous system. This delivery technique is innovative and based on our preliminary data, which supports our hypothesis that CSF delivery of the vector could substantially reduce the required amount of viral vector in order to target both muscle and NS as higher viral vector amount is re- quired for transducting both NS and muscles using IV. In Aim 1, we will determine optimal CSF dosing in wild type mice. We will also test CSF dosing in a mouse model of Duchenne Muscular Dystrophy (the Dup2 mouse model) to ensure that muscle damage does not alter vector spreading. In Aim 2, we will use the Dup2 mouse model to assess the extent to which CSF delivery of a therapeutic vector (AAV9.ACCA) can achieve therapeu- tic effects. The experiments proposed in Aim 3 will compare the ability of IV and CSF delivery routes to target muscles and NS in non-human primates when using a tenfold lower dose compared to previous studies using IV delivery. This collaborative project will be achieved thanks to the combined expertise of the several laborato- ries: Dr. Wein who has generated both the AAV9.ACCA vector and the Dup2 mouse model used in this study; Dr. Flanigan, an expert in gene therapy and neuromuscular disorders, and Drs. Burghes, Arnold and Meyer, world-renown and highly successful leaders in gene therapy and CSF delivery techniques. The impact of this study cannot be overstated, as the results would be of high interest globally for a very large patient community, as well as researchers working on other neuromuscular disorders. The results from this study could be applied to many neuromuscular disorders.


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: 2025 ( Subtotal = -$10,992 )
2025	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	10/10/2024	NON-COMPETING CONTINUATION	-$10,992
														Subtotal = -$10,992

Issue Date FY: 2023 ( Subtotal = $321,752 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/19/2023	NON-COMPETING CONTINUATION	$321,752
														Subtotal = $321,752

Issue Date FY: 2022 ( Subtotal = $345,017 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/6/2022	NON-COMPETING CONTINUATION	$345,017
														Subtotal = $345,017

Issue Date FY: 2021 ( Subtotal = $382,447 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/19/2021	NON-COMPETING CONTINUATION	$382,447
														Subtotal = $382,447

Issue Date FY: 2020 ( Subtotal = $487,911 )
2020	2020	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/21/2020	NON-COMPETING CONTINUATION	$487,911
														Subtotal = $487,911

Issue Date FY: 2019 ( Subtotal = $459,656 )
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/9/2019	NEW	$459,656
														Subtotal = $459,656

Grand Total All Awards = $1,985,791

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Alternative delivery of adeno-associated virus therapeutic vector for the treatment of neuromuscular disorders

Award Number: R01AR073908

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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