# Toward a CRISPR-AAV Gene Therapy Targeting a Mitochondrial Anchor to Treat Progressive Multiple Sclerosis

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $232,813

## Abstract

The premise of this R21 is to translate the rodent work in the Chiu laboratory to a gene therapy for
progressive multiple sclerosis (MS). MS is the major demyelinating disease for neurological disability in young
adults in the US. MS starts with an early phase but converts into a late or progressive phase that is currently
incurable. From 2015-2019, the Chiu laboratory identified a specific mechanism for neurodegeneration in
progressive MS by studying the progressive phase of two different mouse models (Shiverer and EAE/NOD)
that mimic the complex range of human MS. The culprit is an axon-specific mitochondrial anchoring protein
called syntaphilin (SNPH), which is excessively upregulated as the disease transitions into the late phase. The
result is excessive braking of mitochondria along the axons that disrupts recycling of mitochondria, leading to
degradation in mitochondrial health that ultimately kills the axons. In the last 4 years, the Chiu laboratory
demonstrated that the two models of progressive MS can be rescued by constitutive SNPH-KO intervention.
The goal of this R21 is to see if similar rescue can be achieved by CRISPR-AAV gene therapy. We have
designed CRISPR molecular scissors to cut-and-silence SNPH and will package the scissors into novel AAV
vectors that can penetrate the blood-brain-barrier by single-dose intravenous injections. In Aim #1, we will use
a CNS vector (AAV-PHP.eB) to treat the Shiverer mouse to rescue the cerebellum. In Aim #2, we will use a
PNS vector (AAV-PHP.S) to treat the EAE/NOD mouse to rescue the spinal cord by promoting remyelination.
Conclusion – There are many FDA-approved drugs for the early phase of MS, but no effective treatments are
available once the disease progresses into the late phase. In the last 4 years, the Chiu laboratory has identified
excessive braking of mitochondria as a cause for killing axons in the progressive phase using two rodent
models. This R21 grant will translate 4-years of rodent work into a possible gene therapy to treat human
progressive MS.

## Key facts

- **NIH application ID:** 10059282
- **Project number:** 5R21NS114844-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHING Yan CHIU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $232,813
- **Award type:** 5
- **Project period:** 2019-12-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10059282

## Citation

> US National Institutes of Health, RePORTER application 10059282, Toward a CRISPR-AAV Gene Therapy Targeting a Mitochondrial Anchor to Treat Progressive Multiple Sclerosis (5R21NS114844-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10059282. Licensed CC0.

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