# Optimal Window of Opportunity for Granulosa Cell Gene Therapy in Galactosemia

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $253,167

## 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, affected women
invariably show ovarian damage and fertility impairment representing the greatest burden of their disease.
There are currently no satisfactory treatments available to prevent this complication. Recently, insights into
the underlying pathophysiology and innovative technological advancements have become available, and
options for curative treatment have emerged. Using this momentum, we aim to develop a treatment to
prevent fertility impairments. We aim to 1) develop a non-viral nucleic acid therapy approach that targets the
ovary and 2) determine the optimal timing to rescue the ovarian function. Folliculogenesis is driven by the
cross-talk between oocytes and granulosa cells. Restoration of GALT activity in these cells could possibly
rescue the ovarian damage.
In this pilot grant application, we will explore a new modality of gene therapy using nanoparticles
encapsulating episomal GALT cDNA within a non-viral expression vector. This will include determination of
the optimal cationic polymer layer for delivery of episomal DNA plasmids expressing GFP or GALT to
granulosa cell lines and the addition of ligands to encourage uptake and promote specificity.
In addition, we will determine the optimal window of opportunity for this treatment. A prenatal origin has been
considered for decades whereas the data currently available, albeit scarce, favor a postnatal origin. There is
undoubtedly early damage, but whether treatments aimed to prevent ovarian damage needs to be started in
the neonatal period, or treating in infancy or adolescence would suffice, is not clear. This will be studied using
the zebrafish model for classic galactosemia that mimics the fertility impairments and is suitable for studies
through development. Zebrafish reproduction is regulated by the brain-pituitary-gonadal axis, comparable
to the human situation. For this purpose, RNA-seq, histology/immunohistochemistry of follicole
development and single cell RNA-seq of oocytes and granulosa cells at 4 developmental stages will
be studied. These studies will uncover developmental stage and cell-specific alterations in the affected
ovaries. Distinctive patterns at the different stages are expected to reveal at which stage(s) damage
can be prevented/halted using ovary targeted gene therapy.

## Key facts

- **NIH application ID:** 10787066
- **Project number:** 1R21HD113931-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Gerard Thomas Berry
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $253,167
- **Award type:** 1
- **Project period:** 2024-08-23 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10787066

## Citation

> US National Institutes of Health, RePORTER application 10787066, Optimal Window of Opportunity for Granulosa Cell Gene Therapy in Galactosemia (1R21HD113931-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10787066. Licensed CC0.

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