# Gene therapy targeting striatal dysfunction for Parkinson’s disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $559,773

## Abstract

Project Summary
Parkinson’s disease (PD) is characterized by motor abnormalities primarily caused by loss of midbrain
dopamine (DA) cells, which significantly modulate striatal neurons. DA depletion is thus associated with altered
function of striatal projection neurons (SPNs). SPN dysregulation is evidenced by significant morphological and
physiological changes, as shown in numerous ex-vivo and in-vivo studies. Furthermore, our studies in primate
models and patients have revealed pathological hyperactivity of SPNs. A key contributor to this hyperactivity is
the excitatory glutamate signaling. This has been recently demonstrated with selective striatal blockade of
NMDARs. The block reduces hyperactivity and controls the altered neuronal responses to DA replacement.
Furthermore, it has significant effects on parkinsonian motor symptoms. Therefore, data support that reducing
NMDAR signaling on SPNs may have therapeutic effects in PD. Given the largely conserved structure of
NMDARs across brain regions, pharmacotherapies are generally limited by widespread drug actions. We
recently tested gene therapies targeting NMDAR subunit expression in the striatum. Our preliminary data
generated with exploratory tests in rodents showed that, indeed, gene knockdown (KD) of GluN2 subunits may
offer a novel therapeutic strategy to improve motor symptoms of PD. Thus, data support advanced preclinical
studies of GluN2 gene KD in non-human primates (NHP) for extensive evaluation of this gene therapy in the
gold-standard model of PD.
In this project we plan to demonstrate “efficacy” of GluN2 gene KD for various motor and cognitive symptoms
of PD. The studies will use primate MPTP models and shRNA viral vector injections in the striatum to suppress
gene expression of GluN2 in SPNs. A battery of motor and cognitive tests will be used over a prolonged term
post-virus administration to determine stable, chronic effects. Taking advantage of PD modeling in NHPs,
different disease stages will also be evaluated. We also include additional outcome measures to evaluate
“safety” of targeting the proper assembly of NMDAR in the striatum. Finally, we will validate this gene therapy
with electrophysiology data demonstrating specific effects on altered SPN activity, and applying optogenetics.
for cell resolution in NHP recordings. Overall, the research strategy in this proposal is based on optimal animal
models, viral vectors of proven efficiency, extensive testing of motor, cognitive, and other behaviors, and
precision tools for electrophysiology. We expect that results of these studies demonstrate efficacy and safety
with translational data to support further development of striatal GluN2 gene therapy for PD.

## Key facts

- **NIH application ID:** 10423704
- **Project number:** 1R01NS126924-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Stella M Papa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,773
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10423704

## Citation

> US National Institutes of Health, RePORTER application 10423704, Gene therapy targeting striatal dysfunction for Parkinson’s disease (1R01NS126924-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10423704. Licensed CC0.

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