# Immunomodulation Approaches to Improve Safety And Efficacy of Gene Therapy Treatment in Friedreich’s Ataxia

> **NIH NIH U01** · UNIVERSITY OF FLORIDA · 2021 · $792,500

## Abstract

Project Summary / Abstract
 Friedreich’s ataxia (FA) is the most common form of hereditary ataxia, affecting ~1 in every 50,000 people
in the US. FA is an autosomal recessive condition caused by the inheritance of a GAA trinucleotide repeat
expansions in the frataxin (FXN) gene, which results in reduced levels of FXN in mitochondria. Clinical
manifestations appear between the ages of 8 and 16 as a multisystem disorder, primarily affecting cardiac and
nervous system. FA is steadily progressive and is characterized by diminished quality of life (QOL) and
premature death, usually caused by ventricular arrhythmia. There is currently no effective treatment.
 Gene replacement using recombinant adeno-associated viral vectors (rAAV) carrying the human FXN gene
is a promising therapeutic strategy for FA as shown by our group and others. Our group has conducted
toxicology and biodistribution studies in support of the first-in-human gene therapy study for the treatment of
FA. The IND will be submitted in 2020 Q2 and we expect to enroll the first patient immediately after approval.
 However, a critical unresolved challenge for the success of gene therapy is the host immune response to
the vector capsid. Administration of rAAV vectors carrying a transgene elicits cellular and adaptive immune
responses against the vector capsid. Exaggerated immune responses can lead to safety concerns and impact
longevity of expression, as well as contribute to loss of the therapeutic effect. In addition, preclinical data from
our lab and others suggest that prior natural exposure to AAV (pre-existing immunity), can lead to severe
infusion reactions and diminished therapeutic efficacy with subsequent AAV exposure. Current AAV-mediated
gene therapy trials must consider a single exposure to the therapeutic vector at a dose below the toxic level
and exclude subjects with pre-existing AAV immunity. Our hypothesis is that a more effective dose could be
achieved safely by incremental dosing of AAV with multiple lower AAV doses over time. Our extensive
preclinical and clinical data demonstrate that B-cell depletion with rituximab and sirolimus in association with
AAV delivery prevents formation of antibodies and confirm our hypothesis. However, prolonged use of
rituximab has been associated with rare but devastating adverse events. In this U01 application, we propose to
improve the overall efficacy and safety of the planned FA gene therapy program by identifying an optimal
immunomodulation regimen to prevent immune responses against the AAV capsid, which will allow for safe
repeated administration of AAV (Aim 1) and therapeutic AAV administration in subjects’ with pre-existing
immunity (Aim 2). We anticipate that the proposed studies will have a major impact on the application of gene
therapy approaches not only for FA, but for a wide array of neuromuscular genetic disorders.

## Key facts

- **NIH application ID:** 10106742
- **Project number:** 1U01NS116752-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Manuela Corti
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $792,500
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106742

## Citation

> US National Institutes of Health, RePORTER application 10106742, Immunomodulation Approaches to Improve Safety And Efficacy of Gene Therapy Treatment in Friedreich’s Ataxia (1U01NS116752-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10106742. Licensed CC0.

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