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

> **NIH NIH UG3** · GEORGE WASHINGTON UNIVERSITY · 2022 · $557,017

## Abstract

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 acro...

## Key facts

- **NIH application ID:** 10439890
- **Project number:** 5UG3TR003897-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Anne Eliane CHIARAMELLO
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $557,017
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439890

## Citation

> US National Institutes of Health, RePORTER application 10439890, Emerging therapeutic candidates for rare maternally inherited mitochondrial diseases with shared etiologies (5UG3TR003897-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439890. Licensed CC0.

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