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Emerging therapeutic candidates for rare maternally inherited mitochondrial diseases with shared etiologies

Award Number: UH3TR003897
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/07/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Emerging therapeutic candidates for rare maternally inherited mitochondrial diseases with shared etiologies - Project Summary/Abstract This UG3/UH3 proposal is in response to RFA-TR-20-031-Basket Clinical Trials of Drugs targeting Shared Molecular Etiologies in Multiple Rare Diseases. The proposed studies focus on two ultra-rare maternally inherited mitochondrial diseases MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) and LHON-Plus (Leber’s hereditary optic neuropathy-Plus). Both diseases are among those studied by the Rare Diseases Clinical Research Network. Patients do not have access to effective therapeutic intervention, resulting in significant disability, morbidity, and premature death. The devastation wrought by these diseases underscores the urgency to address this unmet medical need and develop novel therapeutic candidates. However, their ultra-rare prevalence makes it challenging to recruit an accrued number of MELAS and LHON- Plus patients to clinical trials. Thus, the proposed basket clinical trial design will combine these two ultra-rare populations to provide proof-of-concept of its feasibility for divergent patient populations. MELAS and LHON-Plus patients exhibit divergent and overlapping clinical neurological and non-neurological symptoms. They are caused by a maternally inherited pathogenic variant that results in a defective oxidative phosphorylation pathway responsible for mitochondrial ATP synthesis. Both diseases share the molecular etiology of Complex I deficiency, causing ATP deficiency and chronic energy deficit. We designed a novel two-pronged pharmaco-epigenomic strategy to increase ATP output in MELAS and LHON-Plus patients. Our pre-clinical studies using ex-vivo patient-derived fibroblasts demonstrate the feasibility of our lead compound to promote mitochondrial recovery in MELAS and LHON-Plus patient’s fibroblasts. The proposed multi-PI studies combines the cross-disciplinary strengths of the George Washington University School of Medicine and Health Sciences and Children’s National Medical Center, a referring site for the North American Mitochondrial Disease Consortium. This partnership is funded by an NIH Clinical and Translational Science Award UL1 Program providing a robust infrastructure for the proposed studies. Aim 1 (UG3 phase) focuses on translational MELAS and LHON-Plus studies and submission of an IND protocol to the FDA. Aim 2 (UH3 phase) focuses on a basket clinical trial with MELAS and LHON-Plus to: 1) provide proof-of-concept that the basket design can be applied to divergent ultra-rare diseases; 2) advance the dataset for safety and pharmacokinetics/pharmacodynamics of our lead compound for a larger number of patients than in a conventional clinical trial setting; and 3) gather outcomes and practical information for optimizing the design of future basket clinical trial. Our innovative design lies in applying the concept of basket clinical trial not only to multiple diseases with a common molecular target, but also to groups with similar ex-vivo fibroblasts response to butyrate across these diseases to improve our ability to evaluate our therapeutic drug in ultra-rare disease populations.


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: 2026 ( Subtotal = $649,230 )
2026	2026	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	002	5	8/12/2026	SUPPLEMENT FOR EXPANSION	$649,230
2026	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	000	5	3/25/2026	NON-COMPETING CONTINUATION	$0
2026	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	001	5	6/22/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $649,230

Issue Date FY: 2025 ( Subtotal = $916,686 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	001	5	7/31/2025	NON-COMPETING CONTINUATION	$916,686
2025	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	000	4	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $916,686

Issue Date FY: 2024 ( Subtotal = $932,696 )
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	001	4	9/11/2024	NON-COMPETING CONTINUATION	$932,694
2024	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	000	3	4/2/2024	EXTENSION WITH OR WITHOUT FUNDS	$2
														Subtotal = $932,696

Issue Date FY: 2023 ( Subtotal = $957,084 )
2023	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center for Advancing Translational Sciences	000	3	8/29/2023	EXTENSION WITH OR WITHOUT FUNDS	$957,084
														Subtotal = $957,084

Grand Total All Awards = $3,455,696

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Emerging therapeutic candidates for rare maternally inherited mitochondrial diseases with shared etiologies

Award Number: UH3TR003897

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 05/07/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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