# Modeling mtDNA Disease in vivo

> **NIH NIH R24** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $629,508

## Abstract

Mitochondrial disease has a minimum prevalence of at least 1 in 5000 adults, with few or no effective
treatments. Mitochondrial disease patients demonstrate enormous biological variation and diverse disorders.
These include neurologic, cardiac, endocrine, kidney, visual, hearing, blood, and skeletal muscle systems.
Imaging and basic science of mitochondria showcase how this highly dynamic organelle responds differentially
to extrinsic, intrinsic and unknown biological signals from roles in metabolism, organ homeostasis, apoptosis
and aging. One unique feature of mitochondria is their dual genome nature where both nuclear and
mitochondrial genomes contribute to its form and function. Sequence variations in either genome each
contribute to human mitochondrial genetic disease. The mitochondrial genome is highly conserved in all
vertebrates, for example the zebrafish mitochondrial genome is nearly identical in size (16kb+) and encodes
the same complement of genes that are organized in the same order as the human mitochondrial genome. A
key bottleneck in the field has been the historical lack of mitochondrial DNA (mtDNA) gene manipulation tools
that has greatly restricted the options for studying the differential roles of genetic variation in biology and
disease. However, the advent of mtDNA base editors has enabled a series of new cellular and animal models.
With advanced methods and effective delivery, near-complete editing efficiency capable of introducing over
80% programmed editing efficiency in the pioneering animal the zebrafish (Danio rerio) is now possible,
enabling the establishment of the first designer in vivo models of mtDNA disease.
 This research resource project will be accomplished in three aims: 1) Generating animal models of
mtDNA disease using the established mitoFUSXTBE cytosine base editor. Designer models with single
nucleotide variants will be generated in both protein-coding and tRNA mitochondrial genes. 2) To enhance the
kind of alleles that can be modeled and to develop new, tissue-specific mtDNA animal models, mtDNA
modeling work will be expanded using new mitoFUSXTBE adenine base editor. 3) Community engagement for
allele selection and to enhance access to these new models through education, outreach and sharing plans.
 The outcomes of this work will include a series of validated zebrafish lines harboring designer mtDNA
variants suitable for hypothesis testing as well as discovery science. The molecular toolbox will also be
optimized for utility in helping generate other animal models from work by mitochondrial scientists in the field.
Together, these gene editors and in vivo avatars will enable new approaches for diagnoses and therapies for
these terrible diseases.

## Key facts

- **NIH application ID:** 10767530
- **Project number:** 1R24OD035577-01
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Stephen Carl Ekker
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $629,508
- **Award type:** 1
- **Project period:** 2024-09-16 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767530

## Citation

> US National Institutes of Health, RePORTER application 10767530, Modeling mtDNA Disease in vivo (1R24OD035577-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10767530. Licensed CC0.

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