# Tissue Engineered Nigrostriatal Pathway for Anatomical Tract Reconstruction in Parkinson's Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $563,729

## Abstract

ABSTRACT
Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects 10 million people worldwide.
Its motor symptoms result from selective degeneration of dopaminergic neurons in the substantia nigra pars
compacta, leading to a loss of their long-projecting axonal inputs to the striatum. Conventional cell therapy
involves implanting dopaminergic neurons into the striatum; however, this strategy disregards the important
systems-level implications of the native neuroanatomy. Pathway reconstruction strategies aim to address this
limitation by replacing both neurons and axonal fibers in a manner that restores the anatomy – and hence
circuit function – of the lost pathway. We have developed a reconstruction strategy whereby tissue-engineered
nigrostriatal pathways (TE-NSPs) are pre-fabricated in vitro featuring a population of human stem cell-derived
dopaminergic neurons and their long-projecting axonal tracts encased within a biocompatible tubular hydrogel.
TE-NSPs may be implanted to directly replace the pathway, supplying both dopaminergic neurons to the nigra
and providing axonal inputs to the striatum, thereby restoring crucial interconnectivity of the basal ganglia. In
this proposal, we will answer a fundamental and neglected question in cell therapy for PD by characterizing
whether pathway reconstruction with the TE-NSPs enables improved restoration of motor function compared to
conventional striatal grafts in a rat model of PD. Our overarching hypothesis is that TE-NSPs will lead to more
robust motor recovery than striatal grafts through a mechanism involving the reestablishment of physiological
innervation and striatal dopamine regulation patterns more closely matching those of native basal ganglia. This
hypothesis will be tested over three Aims: (1) Establish the ability of TE-NSPs to reconstruct basal ganglia
circuitry via axonal-dendritic synaptic integration; (2) Demonstrate real-time efficacy of TE-NSPs in restoring
nigrostriatal functionality; (3) Assess the influence of TE-NSP activity on motor recovery. TE-NSP mechanisms
and efficacy will be compared to hydrogel-encased nigral or striatal grafts, acellular hydrogel implants, as well
as non-implant and non-lesioned animals out to 24 weeks post-implantation. Motor function will be evaluated
with rotational, forelimb asymmetry and adhesive removal tests. Innervation and connectivity patterns will be
assessed with immunohistochemistry and monosynaptic rabies tracing, while ex vivo and in vivo voltammetry
and [18F]F-DOPA positron emission tomography will be used to analyze real-time dopamine release and
uptake in the striatum. We will also employ chemogenetics to silence neural activity in TE-NSPs to test the
effects on motor function. Overall, TE-NSPs address a crucial gap in clinical treatment by providing a means to
directly replace the nigrostriatal pathway, which may yield significant benefits over other methods by providing
properly-regulated dopamine in the stri...

## Key facts

- **NIH application ID:** 10915583
- **Project number:** 5R01NS127895-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel Kacy Cullen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,729
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915583

## Citation

> US National Institutes of Health, RePORTER application 10915583, Tissue Engineered Nigrostriatal Pathway for Anatomical Tract Reconstruction in Parkinson's Disease (5R01NS127895-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10915583. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*