# Macrophage-Mediated Gene Delivery of Neurotrophic Factors in Parkinson's Disease

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2021 · —

## Abstract

Abstract
The development of a neuroprotective therapy for Parkinson's disease (PD) would be a major therapeutic
advance, particularly for our veterans. Glial cell line-derived neurotrophic factor (GDNF) has been shown to be
the most potent protective trophic molecule to dopamine (DA) neurons affected in PD. GDNF requires CNS
delivery as it does not cross the blood-brain barrier (BBB). Unfortunately, clinical trials of GDNF therapy in PD
patients have given mixed results. It is challenging to deliver therapeutic levels of GDNF to all degenerating
nigrostriatal neurons using traditional surgical approaches due to the large target area in the human brain and
the poor brain tissue penetration of this molecule. We have developed a novel approach capable of resolving
these problems: hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated GDNF
delivery. This unique approach takes advantage of macrophages’ natural property of homing to sites of
neuronal degeneration, capitalizes on our powerful macrophage-specific synthetic promoter (MSP), and
implements recent advances in HSC gene therapy. Our previous work using conventional HSCT reproducibly
demonstrated the effectiveness of our approach in various (acute and chronic, and neurotoxin induced and
genetic) mouse models of PD. However, conventional HSCT requires toxic preconditioning such as irradiation
and thus may not be suitable for our veterans with PD. In the last funding cycle, we introduced our newly
developed novel non-cytotoxic HSCT method. Using this novel system, we again demonstrated that genetically
engineered HSC-derived macrophages infiltrate the brain parenchyma and accumulate at diseased sites to
provide sustained focal GDNF delivery that leads to dramatically reduced degeneration of DA neurons in the
substantia nigra of PD mice. Critically, this protection ultimately results in amelioration of motor and non-motor
dysfunction and is achievable with little apparent adverse effects. In this grant application, we propose to study
the dose-effect relationship of this novel HSCT-based approach to identify key correlates of protection and the
optimum therapeutic dose. The efficacy of this novel intervention will be validated in an additional model of PD.
Finally, single-cell RNAseq sequencing will be applied to delineate the molecular and cellular mechanisms
underlying this novel neuroprotective therapy. The proposed study will provide another important step in the
development of our innovative disease-modifying treatment for PD.

## Key facts

- **NIH application ID:** 10125790
- **Project number:** 2I01BX000737-09A2
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** SENLIN LI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2012-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125790

## Citation

> US National Institutes of Health, RePORTER application 10125790, Macrophage-Mediated Gene Delivery of Neurotrophic Factors in Parkinson's Disease (2I01BX000737-09A2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10125790. Licensed CC0.

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