# Improving AAV-based gene therapy for Krabbe Disease

> **NIH NIH F30** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $52,694

## Abstract

Abstract
 Krabbe’s Disease (KD) is a rare inherited leukodystrophy caused by mutations in the GALC gene
encoding the lysosomal enzyme, galactosylceramidase (GALC). Lack of functional GALC leads to global
demyelination and neurodegeneration. Untreated KD presents in infants as developmental delay and
regression, failure to thrive, and ultimately death by 2-3 years of age. KD is treated with hematopoietic stem
cell transplantation (HSCT) which slows the progression of disease and prolongs life expectancy into the
teenage years, but it is not a cure. Adeno-associated viruses (AAV) have been utilized successfully as gene
therapy treatment vectors in numerous pre-clinical and clinical trials. The initial success of AAV gene therapy in
diseases primarily affecting neuronal cells led to investigations of their efficacy in monogenic diseases affecting
multiple cells types such as KD. The Bongarzone lab previously developed a treatment protocol using AAV9-
GALC to correct the deficiency in the Twitcher murine model of KD. This treatment completely prevented
disease development for the first 6-8 months of life, such that AAV-treated mice were nearly indistinguishable
from wild-type mice. Despite these promising results, our study also revealed a slow decline in treatment
efficacy over time, including development of disease signs and focal demyelinating plaques in mice of
advanced age; similar findings have been noted by other investigators as well. No alternative modifications to
improve gene therapy have been proposed thus far.
 The overarching goal of this application is to establish whether gene therapy efficacy is declining due to
exhaustion of AAV DNA in the adult brain and how to optimize gene therapy treatment efficacy and duration in
Twitcher mice. As AAV-GALC DNA exists as a non-replicating extra-chromosomal episome after entering a
cell, we hypothesize the decline in treatment efficacy is caused by loss of therapeutic vector in replicating cells,
particularly oligodendrocyte precursors, in the Twitcher brain, which leads to a decrease in the average AAV-
GALC episomes per cell over time. This hypothesis will be investigated by treating mice shortly after birth with
AAV9-GALC at decreasing dosages and then observing how long the treatment is efficacious based on clinical
score, survival, as well as biochemical and histological analyses. We will then examine if redosing utilizing
oligodendrocyte targeted AAV (AAV-001) later in life, but prior to disease sign onset, delays or prevents
development of disease signs. Finally, we will determine if utilizing AAV-001 singly will increase the efficacy
and duration of treatment in comparison to AAV9. This study is important because we need to better
understand what happens to episomal AAV DNA long term before attempting to use AAV based therapies to
treat KD patients. Furthermore, our findings will have the intrinsic impact of better characterizing how episomal
AAV DNA behaves in similar monogenic disorders...

## Key facts

- **NIH application ID:** 10653237
- **Project number:** 5F30HD103447-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Gregory J Heller
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $52,694
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653237

## Citation

> US National Institutes of Health, RePORTER application 10653237, Improving AAV-based gene therapy for Krabbe Disease (5F30HD103447-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10653237. Licensed CC0.

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