# Advancing a novel experimental mRNA-based therapy for Classic Galactosemia

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $190,625

## Abstract

PROJECT SUMMARY / ABSTRACT
 Hereditary deficiency of galactose-1-phosphate uridylyltransferase (GALT, E.C. 2.7.7.12) activity in humans can
lead to a potentially lethal disease called Classic Galactosemia (OMIM 230400). Despite the life-saving consequences of
newborn screening, early diagnosis, and a galactose-restricted diet, many patients with Classic Galactosemia suffer later in
life from complications including growth, neuropsychological, and speech delays as well as primary ovarian insufficiency
(POI). There are currently no satisfactory treatments available to prevent/alleviate any of these complications. The precise
pathogenic mechanisms of these complications remain unclear, although aberrant galactosylation of glycoproteins/lipids
and inositol phospholipid signaling caused by the chronic exposure to toxic intermediates of the blocked galactose metabolic
pathway in susceptible tissues have been proposed. But regardless of the proposed mechanisms and any of the associated
controversies, no one will debate that the root cause for the disease is the deficiency of GALT enzyme activity in the affected
tissues. Therefore, we collaborated with colleagues at Moderna Inc. to explore if we could augment functional GALT
activity in an animal model of Classic Galactosemia with an innovative GALT mRNA therapy. Specifically, we hypothesize
that targeted augmentation of hepatic GALT activity by GALT mRNA therapy is sufficient to restore whole-body galactose
metabolism and ameliorate the disease-relevant phenotypes in Classic Galactosemia. Preliminary results showed that
intravenous injection of human GALT mRNA in GalT-/- mice resulted in hepatic expression of active, long-lasting GALT
enzyme, which rapidly and effectively reduced gal-1P in liver and some other peripheral tissues and significantly lowered
plasma galactose. Yet, it is too early to tell if biomarker correction can lead to actual phenotypic improvements. Therefore,
we aim to demonstrate in this application that sole augmentation of hepatic GALT activity in a mouse model of
Galactosemia is sufficient to ameliorate the disease-relevant phenotypes (Aim 1) and restore normal whole-body galactose
metabolism (oxidation) (Aim 2). If we are successful, we will be able to advance this experimental mRNA therapy to
clinical trials (high reward), and this could bring an innovative therapy to address the unmet medical needs of the patients -
a high-impact outcome. Moreover, the critical information about the optimal timing of treatment and predictive values of
the biomarkers to be revealed in the proposed work will render significant insights to the disease process and guide the
development of other modalities, including gene therapy. Last but not least, if we can show that restoration of galactose
metabolism in the liver can result in significant improvement of whole-body galactose oxidation, this could lead to diet
relaxation (high impact) and such therapeutic strategy could be applied to other metabo...

## Key facts

- **NIH application ID:** 10470273
- **Project number:** 5R21HD104056-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kent Lai
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2021-08-17 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470273

## Citation

> US National Institutes of Health, RePORTER application 10470273, Advancing a novel experimental mRNA-based therapy for Classic Galactosemia (5R21HD104056-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10470273. Licensed CC0.

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