# MTR1: A Dinucleotide Substrate Enhancement and Molecular ByPass Therapy for Thymidine Kinase 2 Deficiency

> **NIH NIH R44** · MITORAINBOW THERAPEUTICS, INC. · 2022 · $907,760

## Abstract

SUMMARY
Thymidine Kinase 2 (TK2) is a mitochondrial enzyme that performs the first of the sequential phosphorylation
steps that produce deoxythymidine triphosphates and deoxycytidine triphosphates, which are required for
mitochondrial DNA synthesis. Genetic deficiency of TK2 results in depletion of mitochondrial DNA and loss of
functional mitochondria. These events result in TK2 deficiency, a disease that manifests as progressive
myopathy, primarily of skeletal muscle and the diaphragm, and occasional neurological disorders such as
seizures. The most aggressive form of the disease has its onset in infancy, and most of these toddlers die within
a year of diagnosis.
Elucidation of the pathogenesis of TK2 deficiency has led to two potential treatment options that were evaluated
under a compassionate use program: (1) substrate enhancement therapy and (2) molecular bypass therapy.
Substrate enhancement therapy consists of administering combinations of deoxycytidine and deoxythymidine
(dC+dT) and molecular bypass therapy consists of administering combinations of dC monophosphate and dT
monophosphate (dCMP+dTMP). Either combination pair was shown to reverse disease progression and
lengthen the lives of patients with TK2 deficiency. The combination of dC+dT is currently in clinical development
and is administered at very high doses (ranging from approximately 8 to >50 grams daily) in patients who have
difficulty swallowing, a subset of whom require feeding tubes to eat. Furthermore, dC+dT offers the benefit of
substrate enhancement therapy, but not molecular bypass therapy.
MitoRainbow is pursuing preclinical development of a MTR1, a single-agent dinucleotide that is metabolized to
all four therapeutic compounds (dC, dT, dCMP and dTMP) in vivo, thus providing both substrate enhancement
and molecular bypass therapies. MTR1 is administered by parenteral administration at <1% the dose of oral
dT+dC. This approach is anticipated to provide superior bioavailability and ease of use to reach the threshold
of effectiveness to treat TK2 deficiency.
In this Direct-to-Phase II SBIR we will (1) manufacture MTR1 drug substance (Aim 1), (2) perform a preclinical,
non-GLP PK, and acute tolerability study in minipigs (Aim 2), and (3) conduct IND-enabling bioanalytical, PK,
and safety studies (Aim 3). Completion of these Aims will provide sufficient data for MitoRainbow to file an IND
with the FDA, and to initiate clinical investigations of MTR1 drug product in patients with TK2 deficiency.

## Key facts

- **NIH application ID:** 10547364
- **Project number:** 1R44GM142348-01A1
- **Recipient organization:** MITORAINBOW THERAPEUTICS, INC.
- **Principal Investigator:** Curtis Cui
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $907,760
- **Award type:** 1
- **Project period:** 2022-09-17 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547364

## Citation

> US National Institutes of Health, RePORTER application 10547364, MTR1: A Dinucleotide Substrate Enhancement and Molecular ByPass Therapy for Thymidine Kinase 2 Deficiency (1R44GM142348-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10547364. Licensed CC0.

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