# A Clinical Trial of AAV2-BDNF Gene Therapy in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $1,201,473

## Abstract

Project Summary/Abstract: We propose to conduct a first-in-human clinical trial of BDNF
gene therapy in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), aiming to
reduce neuronal loss and to activate neuronal function. BDNF (Brain-Derived Neurotrophic
Factor) is actively produced and utilized in cortical circuits throughout life to sustain neuronal
function and circuits. In animal models of AD, BDNF builds new synapses, prevents neuronal
death and activates neurons; thus, BDNF offers the potential to slow or actually reverse
cognitive decline in established AD and MCI. Proof-of-concept studies have been performed in
mice, rats and rhesus monkeys.
Because BDNF is a relatively large and polar protein that does not cross the blood brain barrier,
we will use intraparenchymal gene therapy to deliver BDNF directly into the entorhinal cortex.
BDNF will be neuronally trafficked into the hippocampus. BDNF will be delivered using adeno-
associated serotype 2 vectors (AAV2), which have now been utilized in hundreds of patients in
CNS gene therapy trials. We will utilize start-of-the-art methods for gene delivery, employing
real-time MR guidance and convection-enhanced delivery (CED) in collaboration with the world
leaders in this technology at Ohio State University (OSU).
A total of 12 patients (6 AD and 6 MCI) will be recruited from two clinical sites: UCSD and Case
Western. All patients will undergo gene delivery at OSU. The primary outcome measure will be
safety, together with secondary cognitive outcome measures that reflect memory-specific and
global cognitive measures. Serum, CSF and imaging biomarkers will be collected. If AAV2-
BDNF gene delivery is safe and well-tolerated, and exhibit possible cognitive benefits, we will
advance to Phase 2 trials. An IND for this program is under review by the FDA, and the trial will
begin upon FDA clearance. Two dose groups will be studied: 3x1011 vg/ml and 1x1012 vg/ml.
Relevance: Effective disease-modifying therapies for AD and MCI have not been identified.
BDNF gene delivery offers the potential to slow or reverse cognitive decline in established AD
by building new synapses, stimulating neuronal function and reducing neuronal death. Our
approach also offers the potential for combination therapy with amyloid- and tau-modifying
therapies.

## Key facts

- **NIH application ID:** 10185291
- **Project number:** 1R01AG071656-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** MARK H. TUSZYNSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,201,473
- **Award type:** 1
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185291

## Citation

> US National Institutes of Health, RePORTER application 10185291, A Clinical Trial of AAV2-BDNF Gene Therapy in Alzheimer's Disease (1R01AG071656-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10185291. Licensed CC0.

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