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Optimizing medium-chain lipids for the treatment of long-chain fatty acid oxidation disorders

Award Number: R01HD103602
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Optimizing medium-chain lipids for the treatment of long-chain fatty acid oxidation disorders - Project Abstract Long-chain fatty acid oxidation disorders (LC-FAODs) are a heterogenous group of disorders characterized by the inability to break down long-chain fatty acids in the mitochondria for energy. The primary tissues affected are liver, heart, and muscle. These disorders are identified at birth through newborn screening programs. Treatment consists of fasting avoidance and replacing long-chain fats in the diet with medium-chain fatty acids (MCFA). Despite decades of orally dosing patients with MCFA-containing oils, it is not understood how MCFA are metabolized by liver, muscle, and heart. Further, the rigor of the experimental evidence regarding the therapeutic efficacy of oral MCFA is low. In mouse models of LC-FAOD, oral MCFA do not improve cardiomyopathy or the capacity for exercise. Human patients likewise still suffer from muscle symptoms and rhabdomyolysis. In the current proposal it is postulated that there are two major problems with current MCFA-based therapies. First, muscle and heart are not equipped to metabolize exogenous MCFA. Second, orally-administered MCFA are nearly completely absorbed by the liver and do distribute to heart and muscle. It is hypothesized that MCFA therapy can be optimized to treat cardiomyopathy and rhabdomyolysis through the exploration of alternative medium-chain lipid species and alternative routes of delivery. The hypothesis is supported by preliminary data showing that heart and muscle prefer carnitine conjugates of MCFA (MC-carnitines) over free MCFAs, and a demonstrated improvement in muscle function of LC-FAOD mice upon subcutaneous injection of an MC- carnitine. This hypothesis will be fully explored in three Specific Aims: 1) Determine the optimal medium-chain lipid species for liver, heart and muscle; 2) Determine the bioavailability and biodistribution of orally versus subcutaneously-administered medium-chain lipids; and 3) Determine the therapeutic efficacy of medium-chain lipids in LC-FAOD mice. Aim 1 is expected to show that liver prefers free MCFA as substrates, while muscle and heart prefer MC-carnitines. The differential preference is proposed to be due to the presence of mitochondrial medium-chain acyl-CoA synthases in liver but not heart or muscle. Aim 2 is expected to demonstrate that subcutaneous delivery of medium-chain lipids greatly increases bioavailability and subsequent biodistribution to the periphery. Finally, in Aim 3, pre-clinical testing of LC-FAOD mouse models is expected to document the therapeutic advantage of the optimized substrates from Aim 1 and the subcutaneous delivery from Aim 2. The results of this project will lay the groundwork for more personalized, symptom-specific application of MCFA- based therapies in LC-FAOD patients.


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 = $305,473 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	5	3/3/2025	NON-COMPETING CONTINUATION	$305,473
														Subtotal = $305,473

Issue Date FY: 2024 ( Subtotal = $335,644 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	4	5/3/2024	NON-COMPETING CONTINUATION	$30,514
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	4	2/20/2024	NON-COMPETING CONTINUATION	$305,130
														Subtotal = $335,644

Issue Date FY: 2023 ( Subtotal = $338,958 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	3	3/3/2023	NON-COMPETING CONTINUATION	$338,958
														Subtotal = $338,958

Issue Date FY: 2022 ( Subtotal = $337,207 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	2	2/9/2022	NON-COMPETING CONTINUATION	$303,486
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	2	4/26/2022	NON-COMPETING CONTINUATION	$33,721
														Subtotal = $337,207

Issue Date FY: 2021 ( Subtotal = $333,705 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	1	3/16/2021	NEW	$333,705
														Subtotal = $333,705

Grand Total All Awards = $1,650,987

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Optimizing medium-chain lipids for the treatment of long-chain fatty acid oxidation disorders

Award Number: R01HD103602

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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