# Restoring Immune Tolerance in a Model of Multiple Sclerosis

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $381,250

## Abstract

Project Summary / Abstract:
 MS is an autoimmune neurodegenerative disease of the central nervous system (CNS) in which the
etiology is not well understood. Although, auto-aggressive CD4+ T cells play a central role, the breakdown of
immune tolerance mechanisms that permits activation of naive myelin-specific T cells is considered an initial
step in the pathogenesis of MS. A number of pivotal studies in rodent models have substantiated that Ag-
specific Tregs have a significant role in modulating autoimmune CNS disease and can be highly effective at
treating MS. Consequentially, there has been a major focus in developing protocols that stimulate Treg
numbers and their function. Unfortunately, successful therapeutic use of Tregs has been limited by the lack of
safe and effective Ag-specific protocols for isolation and expansion that are suitable for translation.
 The AAV gene transfer platform has clearly demonstrated that hepatocyte-restricted transgene
expression from an optimized AAV vector can reliably induce immune tolerance to various therapeutic
proteins. Importantly, tolerance is dependent on achieving and maintaining adequate hepatocyte-restricted
transgene expression that induces Ag-specific CD4+CD25+FoxP3+ Tregs.
 Recently, we have successfully developed a clinically relevant Adeno-associated Virus (AAV)
immunotherapy that is not only capable of preventing the development of EAE, but can also reverse the
neurological symptoms of preexisting disease. This vector-based immunotherapy uses the full-length protein
coding sequence of a myelin-derived protein, which abrogates the need to identify HLA/MHC specific
epitopes, making this unique approach universally applicable. Mechanistically, this process is based on the
induction of immunological tolerance mediated by antigen specific Tregs.
 We hypothesize that a persistent immunological tolerance, independent of MHC restrictions can be
established against three immunogenic myelin proteins, simultaneously. That such tolerance is mediated by
the induction and expansion of Ag-specific Tregs that can prevent development of and reverse existing disease
in the EAE model of MS.
 Aim 1: Develop, optimize and compare in vivo performance of AAV-PLP and -MBP vectors, and assess
 functional suppression of Ag-specific Tregs
 Aim 2: Demonstrate that AAV immunotherapy vectors can prevent or ameliorate disease in genetically
 diverse strains of mice.
 Aim3: Determine the minimum effective vector (MEV) dose for abrogation of disease without an
 adverse immune response or hepatotoxicity.
 Aim 4: Establish a multi-vector / multi-gene immunotherapy platform.

## Key facts

- **NIH application ID:** 9839477
- **Project number:** 5R01AI128074-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Brad E Hoffman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839477

## Citation

> US National Institutes of Health, RePORTER application 9839477, Restoring Immune Tolerance in a Model of Multiple Sclerosis (5R01AI128074-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9839477. Licensed CC0.

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