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Improving AAV-transduction efficiencies for skeletal muscle delivery

Award Number: R21AI151537
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Improving AAV-transduction efficiencies for skeletal muscle delivery - PROJECT SUMMARY Adeno-associated virus (AAV) is the most commonly used gene therapy vector. Currently, FDA has approved two AAV-mediated therapies, and many more are in pipeline. However, there still are challenges to the effective use of AAV vectors. For example, high doses (~1014 vector particles) are necessary for most human applications. Such high vector doses cause tissue toxicity and elicit high levels of anti-transgene antibodies, limiting therapeutic efficacy. High doses also require large injection volumes and/or multiple injections to achieved desired levels of transgene expression. In addition, high manufacturing costs preclude widespread use of this approach. Each of these difficulties can be addressed by increasing the efficiency of AAV transduction and thereby reducing the number of AAV particles necessary to achieve a desired therapeutic outcome. The intramuscular route of vector delivery has key advantages. It helps circumvent the problem of pre- existing antibodies to the AAV capsid, which otherwise prevents efficient transduction. Expression of a transgene from muscle persists for years or decades due the longevity of this tissue. Finally, unlike other tissues targeted to express AAV transgenes such as the liver, the consequences of tissue damage through local inflammation are modest and manageable to address. However, the relative inefficiency with which AAV transduces human and non-human primate muscle tissues necessitates high vector doses. Therefore many challenges to the AAV-based therapies can be addressed by improving the efficiency of muscle-specific transduction. In the Preliminary Studies, we show that AAV9 modified in the variable region VIII with an insulin receptor-binding peptide is dramatically more efficient than wild-type AAV9 in transducing human differentiated muscle cells and mouse muscles in vivo. We propose in Aim 1 to further improve this vector through directed evolution and selection, and to assess the utility of this peptide in the context of other AAV serotypes. We also propose in Aim 2 to verify our hypotheses that by enhancing vector efficiency, we can reduce tissue toxicity, inflammation, and anti-transgene antibody production, thereby increasing the safety and therapeutic efficacy of these vectors. Together, these studies will identify an AAV vector that much more efficiently transduce muscle tissue, and in doing so, they will also address several challenges associated with AAV-mediated gene therapy.


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: 2024 ( Subtotal = -$1,704 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	1/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,704
														Subtotal = -$1,704

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	1/3/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $231,250 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	2	5/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$10,250
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	2	4/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$241,500
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	001	1	4/6/2022	NEW	$0
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	3/23/2022	NEW	$0
														Subtotal = $231,250

Issue Date FY: 2021 ( Subtotal = $277,500 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	4/14/2021	NEW	$277,500
														Subtotal = $277,500

Grand Total All Awards = $507,046

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Improving AAV-transduction efficiencies for skeletal muscle delivery

Award Number: R21AI151537

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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