# Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $394,032

## Abstract

Abstract
Brain-derived neurotrophic factor (BDNF) is a nervous system growth factor that
enhances synaptic plasticity and regulates neuronal function. BDNF gene therapy for
Alzheimer’s disease (AD) is a promising alternative to amyloid- and tau-targeted
therapies: BDNF reduces neuronal degeneration and stimulates neuronal activity in
rodent and non-human primate models of AD. Direct injection of an Adeno-
Associated Virus (AAV) vector into entorhinal cortex mediates safe and long-lasting
BDNF expression, and will soon begin human clinical trials. Although promising,
intraparenchymal AAV-BDNF injection is invasive and treats only a small percentage
of the cerebral cortex. Intrathecal administration of AAV9-BDNF to the cerebrospinal
fluid could solve these problems by broadly treating the entire cortex from a single
minimally invasive infusion. We recently reported that two hours of Trendelenburg
positioning, in which the body lies supine on a reclining table with the head 30°
below the feet, dramatically increases the strength and consistency of gene transfer
to cerebral cortex after intrathecal AAV9 infusion in rats. More than 95% of
transduced cells in cortex are neurons, and gene expression in off-target brain
regions and spinal cord is minimal. This novel delivery method has strong potential
for clinical treatment of AD.
We propose systematic preclinical testing of intrathecal AAV9-BDNF gene therapy
for AD. Aim 1 will test therapeutic efficacy by directly comparing intrathecal and
intraparenchymal AAV9-BDNF infusion in a transgenic mouse model of AD and
analyzing behavioral and anatomical outcomes. Aim 2 will test the safety of
intrathecal AAV9-BDNF infusion at escalating doses and over prolonged treatment
periods in the non-human primate. Aim 3 will enhance the specificity of intrathecal
AAV9-BDNF therapy by testing cell-specific promoters to reduce or eliminate off-
target gene expression. These studies aim to simplify delivery, enhance efficacy, and
increase clinical feasibility of BDNF gene therapy for AD, and will support both
upcoming clinical trials and preclinical development of new gene therapies for AD.

## Key facts

- **NIH application ID:** 10136505
- **Project number:** 5R01AG066080-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael Castle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,032
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136505

## Citation

> US National Institutes of Health, RePORTER application 10136505, Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease (5R01AG066080-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10136505. Licensed CC0.

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