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Developing co-stimulatory blockade as a therapeutic strategy for Duchenne muscular dystrophy

Award Number: R01NS109117
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Developing co-stimulatory blockade as a therapeutic strategy for Duchenne muscular dystrophy - Project summary. The long-term goal of our research is to develop better strategies to manipulate interactions between dystrophic muscle and the immune system, so that the pathology of Duchenne muscular dystrophy (DMD) can be reduced. As our knowledge of the interactions between the immune system and dystrophic muscle has grown, several distinct mechanisms through which immune cells promote damage of dystrophic muscle have been identified. However, we have also learned that specific populations of immune cells, including some macrophage subpopulations and regulatory T-cells, promote muscle growth and regeneration in muscular dystrophy. Because the activation, phenotype and function of immune cells that affect muscular dystrophy are strongly influenced by costimulatory signals that are exchanged between myeloid cells and lymphoid cells, interventions that target costimulatory pathways have the capacity to influence the balance between detrimental and pro-regenerative processes that are mediated by immune cells in dystrophic muscle. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a particularly important costimulatory molecule that influences interactions between immune cells. Manipulation of CTLA4 availability to mediate signaling between myeloid and lymphoid cells greatly influences the magnitude and quality of the immune response to diseased tissue. Our preliminary findings support the hypothesis that administration of a recombinant fusion protein containing CTLA4 profoundly influences the immune response to dystrophic muscle and reduces muscle damage. In the investigation proposed here, we will test that hypothesis, determine the mechanisms through which CTLA4-mediated interventions affect muscular dystrophy and evaluate the safety and efficacy of long- term administration of exogenous CTLA4 in the mdx mouse model of DMD. Aim 1. Test the hypothesis that treatments with CTLA4-immunoglobin fusion protein (CTLA4-Ig) produce long- term reductions in muscle pathology and improve function in mouse models of DMD. Aim 2. Test the hypothesis that CTLA4-Ig acts on both lymphoid and myeloid cells to reduce muscle injury and inflammation and promote a pro-regenerative environment in dystrophic muscle. Aim 3. Assess safety and long-term effects of CTLA4-Ig administration on immune cell function. Together, these findings can enable us to determine whether CTLA4-Ig, a drug that is safe and efficacious for the treatment of other human diseases, can provide a successful, new strategy for treating DMD.


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: 2023 ( Subtotal = $341,250 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/20/2023	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2022 ( Subtotal = $341,250 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/20/2022	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2021 ( Subtotal = $341,250 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/25/2021	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2020 ( Subtotal = $341,250 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/24/2020	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2019 ( Subtotal = $341,250 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/11/2019	NEW	$341,250
														Subtotal = $341,250

Grand Total All Awards = $1,706,250

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Developing co-stimulatory blockade as a therapeutic strategy for Duchenne muscular dystrophy

Award Number: R01NS109117

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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