Addressing shortcomings of AAV genetherapies for the muscular dystrophies

Active Project Grant Awarded Last action

Award ID
P50HD119693
Recipient
Awarding agency
Obligated
$2,637,805

Award facts

Completion date 85% complete
Place of performance
Gainesville, FL 32611, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
This wellstone muscular dystrophy specialized research center is focused on optimizing AAV-mediated gene therapies for duchenne and limb girdle muscular dystrophy. We are developing novel approaches to address deficiencies we have identified in the existing human AAV-gene therapies for the muscular dystrophies. Our first goal (project 1) is to design and optimize miniaturized utrophin-dystrophin chimeric transgenes that can be delivered using a single AAV vector to the skeletal muscles and hearts of animal models of DMD, the human ipsc-derived engineered heart tissues of project 2, and eventually to humans. Secondly, we will work to design and test improved AAV capsids and transgenes in collaboration with project 2 with the goal to reduce immunostimulatory activity. Project 2 will design and test AAV gene therapy for sarcoglycan deficiency. These include the design and optimization of AAV-gene therapy vectors for sgcg-lgmd with enhanced transgene expression and stability, and reduced immunostimulatory activity. Project 2 will evaluate the optimized AAV- sgcg vectors in vivo and demonstrate functional restoration in heart and muscle. Lastly, project 2 will test AAV- transgenes from projects 1 and 2 in a humanized mouse model of anti-AAV immunity for chemokine stimulation, liver toxicity, and t cell mediated capsid responses. Project 3 entails a clinical study that will follow the skeletal and cardiac muscle progression of micro-dystrophin treated boys and sarcoglycan-deficient individuals using non-invasive biomarkers and functional outcomes. These projects will work together for the common goal of improving the safety and efficacy of gene therapies for muscular dystrophies, directly comparing data across projects to ascertain transgene-specific and platform-related results. Project 3 will collaborate with project 1 to perform tissue validation of T1/T2 measures with tissue histology in the dystrophic RAT (MDR). Project 3 will also work with project 1 to characterize the MR response to AAV therapy and assess blood flow in muscles pre- and post-AAV treatment. Project 3 will collaborate with project 2 to provide blood samples that correlate with imaging data. The center will continue to make important contributions to sharing resources, maintaining our shared resource core for all muscular dystrophy researchers. We will also expand our successful training efforts, continue to cultivate our collaborations with patient advocacy groups and industry, and maintain our outreach efforts for the muscular dystrophy community.

Transactions

Action Obligated Date
Amendment $1,290,269
Original award $1,347,536

Subawards

Subrecipient Amount Awarded
University Of California, LOS Angeles The overall objective of the MDSRC Training Core is to provide education and training to basic and clinical scientists and physicians in the physiological and… $49,718
University Of California, LOS Angeles The Spencer Lab at UCLA will be responsible for conducting a comprehensive assessment of immune responses elicited by adeno-associated virus (AAV) vectors. Much… $145,949
Northwestern University Northwestern investigators, McNally, Fullenkamp, and Demonbreun, will contribute to this Wellstone Muscular Dystrophy Specialized Research Center by testing… $242,373
University Of California, LOS Angeles The overall objective of the MDSRC Training Core is to provide education and training to basic and clinical scientists and physicians in the physiological and… $49,718
University Of California, LOS Angeles The Spencer Lab at UCLA will be responsible for conducting a comprehensive assessment of immune responses elicited by adeno-associated virus (AAV) vectors. Much… $142,848
Northwestern University Northwestern investigators, McNally, Fullenkamp, and Demonbreun, will contribute to this Wellstone Muscular Dystrophy Specialized Research Center by testing… $239,769

Quick answers

Who received award P50HD119693?

P50HD119693 was awarded to University Of Florida by National Institute of Child Health and Human Development (National Institutes of Health) on September 25, 2005.

How much is award P50HD119693 worth?

$2,637,805 has been obligated on P50HD119693.

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