# Evaluation of adeno-associated viral (AAV) mediated gene replacement therapy as a therapeutic option for SLC25A4 deficiency

> **NIH NIH F32** · DUKE UNIVERSITY · 2024 · $83,392

## Abstract

Project Summary/Abstract
Disruption of mitochondrial oxidative phosphorylation (OXPHOS) is associated with the development of
biochemical alterations that typically affect tissues with a high energy demand, particularly skeletal and cardiac
muscle. An inherited autosomal recessive skeletal myopathy and hypertrophic cardiomyopathy has been linked
to loss of function of a nuclear DNA-encoded mitochondrial protein, due to a frameshift mutation in solute
carrier family 25, member 4 (SLC25A4; c.523delC, p.Q175RfxX38). SLC25A4 encodes the heart-muscle
isoform of the adenine nucleotide translocator-1 (ANT1, SLC25A4), which in the wild-type state is a critical
component of mitochondrial metabolism. Patients with SLC25A4 deficiency display lactic acidosis, persistent
adrenergic activation, and exertional intolerance secondary to both a general skeletal muscle myopathy as well
as a hypertrophic cardiomyopathy. Ultimately, myocardial thickening and cardiac dysfunction progress to end-
stage heart failure necessitating cardiac transplantation.
There are not currently any disease-modifying therapies available for this patient cohort. However, adeno-
associated viral (AAV) mediated gene replacement therapies have emerged as a powerful strategy for disease
modification of inherited monogenic disorders. The long-term goal of our research is to develop a therapeutic
gene replacement strategy to treat SLC25A4 deficiency. The objective of this proposal is to further characterize
the disease phenotype as well as to synthesize and evaluate the efficacy of a recombinant AAV (rAAV) vector
in an in vitro model of patient-derived cell lines and organoid models. The central hypothesis of this
proposal is that AAV-mediated gene replacement can ameliorate the biochemical and functional effects
of SLC25A4 deficiency and can more decisively prevent disease progression. The specific aims of this
proposal are:
 1. Characterize the SLC25A4 deficiency phenotype in patient-derived cell lines.
 2. Synthesize a recombinant AAV vector for delivery of codon-optimized SLC25A4 cDNA to
 skeletal and cardiac myocytes.
 3. Evaluate the efficacy of AAV-SLC25A4 viral transduction in patient-derived cell lines.
These experiments will improve our understanding of the molecular mechanisms underlying SLC25A4
deficiency as well as allow us to evaluate the efficacy of an AAV platform in a relevant preclinical model.
Moreover, the skills I will acquire during this fellowship will help to establish me as an independent investigator
and a surgeon-scientist focused on the development of translational gene replacement therapies.

## Key facts

- **NIH application ID:** 10934320
- **Project number:** 5F32HL167559-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Abigail Benkert
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $83,392
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934320

## Citation

> US National Institutes of Health, RePORTER application 10934320, Evaluation of adeno-associated viral (AAV) mediated gene replacement therapy as a therapeutic option for SLC25A4 deficiency (5F32HL167559-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10934320. Licensed CC0.

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