# Gene Therapy Delivery for Age-related Neurodegenerative Diseases

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $729,728

## Abstract

Project Summary/Abstract
Age-related neurodegenerative disorders, such as Alzheimer’s disease and related tauopathies, are a major
therapeutic challenge. There are critical brain regions implicated in disease pathogenesis and overtime the
whole or a large portion of the brain is affected. Therefore, both a focal and broad brain treatment approach is
needed to achieve long-term therapeutic benefit. Gene therapy is the use of genetic material to target disease
etiology. Viral vectors are used to deliver therapeutic genes to cells to provide long-lasting intervention from a
single treatment. Recombinant adeno-associated virus (rAAV) vectors are highly used due to their efficient
gene transfer, broad serotype-dependent tropism, low risk of insertional mutagenesis, and long-term transgene
expression in non-dividing cells, such as neurons. AAV9 is currently the most frequently used serotype for
treating neurological disorders as it can be delivered in blood or cerebral spinal fluid to broadly transduce the
brain in a dose-dependent manner. Direct brain injections are effective for focal brain treatments, but are an
invasive procedure. With non-invasive systemic delivery, high vector doses are needed to achieve sufficient
brain transduction in adults. The greater the number of viral particles received increases the risk of severe
immune responses and inhibits use in adults due to manufacturing considerations. We and others have
demonstrated that use of FUS to open the BBB can significantly reduce systemic vector doses and target rAAV
vectors to select brain regions. While promising for focal treatments, this then limits the ability of AAV9 to
efficiently transduce non-targeted brain regions. CSF delivery of AAV9 significantly reduces the amount of
vector needed to achieve equivalent or greater brain transduction compared to systemic delivery and achieves
high CNS transduction relative to the site of injection. Therefore, we predict that IT delivery of AAV9 combined
with transcranial FUS will allow for both focal and broad targeting of gene therapies to the brain and be an
effective delivery approach for age-related neurodegenerative diseases. This grant will develop the use of
combined FUS and IT injection as an efficient delivery method of AAV vectors to the brain, define mechanisms
for this enhancement, determine vector capsid and promoter usage, and test this application in a mouse model
of tauopathy. If we are successful, this approach can be readily translated for treating neurodegenerative
diseases.

## Key facts

- **NIH application ID:** 10849712
- **Project number:** 5R01AG078417-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Rachel M Bailey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $729,728
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849712

## Citation

> US National Institutes of Health, RePORTER application 10849712, Gene Therapy Delivery for Age-related Neurodegenerative Diseases (5R01AG078417-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10849712. Licensed CC0.

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