# Restoring Immune Tolerance in a Model of Multiple Sclerosis

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $457,500

## Abstract

Project Summary / Abstract
 MS is a chronic neuro-inflammatory autoimmune disease that leads to demyelination and damage of
axons. A breakdown of immune tolerance mechanisms that permits activation of naive myelin-specific T cells is
considered an initial step in the pathogenesis. A number of pivotal studies have demonstrated that antigen Ag-
specific Tregs not only have a significant role in modulating autoimmune CNS disease, but can also be highly
effective at treating MS.2-6 Using the clinically proven adeno-associated virus (AAV) platform, we have developed
an immunotherapy that restores Ag-specific tolerance in experimental autoimmune encephalomyelitis (EAE), the
animal model of MS, that is efficient at preventing disease.1 Importantly, we demonstrate the AAV
immunotherapy is capable of suppressing both clinical disease and inflammatory response in mice with
established disease ranging from mild to severe.
 In addition to primary pathogenic antigens implicated in disease initiation, neo-epitopes can emerge as
result of intra- and/or intermolecular epitope spreading during progression of EAE, and MS. The potential for
increasing multiplicity of anti-myelin autoreactivities imposes major difficulties in developing antigen-specific
therapeutic agents for MS. Not only because of the possibility that the primary target antigen and/or emerging
neo-reactivities may differ in different patients, but the that the potentially pathogenic autoreactivities to several
myelin antigens may occur in any one patient at any one time.7 Studies aimed at inhibiting the development or
progression of EAE associated with more than one pathogenic autoreactivity by antigen-specific
immunomodulation targeting have suggested that all relevant autoreactivities should be targeted for maximal
therapeutic effect.
 Unlike other approaches that require ex vivo T cell engineering and/or expansion of TCR/Ag-specific T
cells, by designing the AAV vectors to express the complete protein coding sequence (not just the
immunodominant epitope) of the autoreactive protein, our approach induces Ag-specific Tregs in vivo and
eliminates the need to identify HLA/MHC specific epitopes, making this approach unique and universally
applicable.
 Building on our previous results, the continuing hypothesis to be tested is that stable hepatic expression
of AAV-delivered neuroantigens will establish a robust and persistent immunological tolerance, mediated by the
in vivo induction and expansion of Ag-specific Tregs, can significantly reduce or stop disease progression in the
EAE model of MS.

## Key facts

- **NIH application ID:** 10786145
- **Project number:** 5R01AI128074-07
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Brad E Hoffman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $457,500
- **Award type:** 5
- **Project period:** 2017-01-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786145

## Citation

> US National Institutes of Health, RePORTER application 10786145, Restoring Immune Tolerance in a Model of Multiple Sclerosis (5R01AI128074-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10786145. Licensed CC0.

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