# Engineered AAV vectors for combinatorial treatment of rare genetic brain diseases

> **NIH FDA R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $599,924

## Abstract

Project Summary
AAV-based gene therapy requires the development of safe, efficient, and target-specific vectors. AAV-mediated
gene therapy for peripheral tissues (blood and skeletal muscle) has made great strides, focused mainly on gene
replacement for loss of function diseases. However, there has been little research on dominantly inherited CNS
disorders that are caused by toxic gene products. We have assembled a world class, multi-disciplinary academic
research team supported by our industrial partners to develop innovative AAV-based gene knockdown and
replacement treatments for rare genetic diseases including Spinocerebellar Ataxia Type 7 (SCA7) and valosin-
containing protein (VCP) multisystem proteinopathy. We respond to the RFA Project Objectives and propose
three Specific Aims. In Aim 1, we will design and manufacture new AAV vectors with improved critical quality
attributes (safety, efficacy, target specificity) for gene therapy. We propose innovative neuron specific gene
delivery, temporal control of gene expression and reduced immune responses in the CNS. We have constructed
AAV vectors that express EGFP and mRNA barcodes for improved screening to support our proposed AAV
treatments. In Aim 2, we will develop advanced quantitative analytics by combining next-generation sequencing
and bar-coded AAVs for efficient assessment of in vivo gene delivery in the mouse model. We will screen and
compare AAV-mediated gene expression with different capsid variants using different promoters / enhancers.
Single-cell RNAseq also will be used to assess immunological responses of selected AAV vectors by different
administration routes. In Aim 3, to effectively treat the SCA7 and VCP diseases, we will develop novel AAV
vectors that simultaneously knockdown toxic gene products while replacing normal gene products that are codon
optimized to be unaffected by knockdown. This proposed combinatorial treatment will establish a proof-of-
concept for many other dominant inherited diseases, where loss of normal allele expression due to non-specific
silencing causes its own problems. We have well developed models of the SCA7 and VCP diseases for Aim 3
studies. Our team has great expertise in developing, manufacturing and applying AAV vectors in basic research
and preclinical application. Our published work and preliminary data establish the feasibility and key
methodologies for the proposed research. Critically, we have an established viral production facility and
distribution platform operating out of our UCI Center for Neural Circuit Mapping that supports viral reagent design,
validation, and manufacturing.

## Key facts

- **NIH application ID:** 10694918
- **Project number:** 5R01FD007478-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** VIRGINIA Eunice KIMONIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2023
- **Award amount:** $599,924
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694918

## Citation

> US National Institutes of Health, RePORTER application 10694918, Engineered AAV vectors for combinatorial treatment of rare genetic brain diseases (5R01FD007478-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694918. Licensed CC0.

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