# Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem Cells

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $614,226

## Abstract

ABSTRACT
Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder that primarily affects
neurons in the striatum and cortex, and for which there is currently no effective treatment. HD is caused by a
CAG expansion in the huntingtin gene leading to a polyglutamine (polyQ) expansion in the encoded protein
(HTT), and patients with a CAG expansion greater than 38 repeats exhibit chorea, psychological problems,
and cognitive decline. Expression of mutant HTT leads to selective neuronal dysfunction and degeneration
despite its ubiquitous expression pattern. Recent advances in stem cell research suggest that patient induced
pluripotent stem cells (iPSCs) may provide novel models of disease and new treatments for diseases. These
studies will utilize iPSCs derived from HD patients (HD-iPSCs) as a human model of HD. Using genetic
engineering, we generated an isogenic allelic HD-iPSC series for HD modeling (CAG repeat of 21, 45, 72,
100). To understand the molecular basis for the CAG repeat expansion dependent disease phenotypes in
NSCs, we performed transcriptomic analysis of HD iPSCs and HD neural stem cells (NSCs) compared to
isogenic controls. Differential gene expression and pathway analysis pointed to TGF-β and netrin-1 as the top
dysregulated pathways, and dysregulated genes were enriched for those involved in neuronal development
and the formation of the dorsal striatum. The disrupted striatal and neuronal networks could be modulated to
correct HD phenotypes and provide therapeutic targets. Therefore the isogenic HD-iPSCs with corrected
alleles provides mechanistic insights into the disease process and allows the identification of novel therapeutic
targets for HD. Indeed our studies suggest that factors that lead to the maturation or maintenance of medium
spiny neurons (MSNs) are likely to ameliorate Huntington's disease phenotypes. We have found that netrin
leads to enhanced rate of maturation of MSNs with increased spontaneous electrical activity and increased
levels of DARPP-32. We will investigate the following aims in this application: Specific Aim 1. We will
characterize the cellular and functional deficits in normal iPSCs, HD-iPSCs, and genetically corrected HD-
iPSCs differentiated into medium spiny neurons using “omics” approaches; Specific Aim 2. Using DARPP-32
genomic elements that direct gene expression specifically in mature MSNs, we will develop a marker of mature
MSNs and identify factors that mediate differentiation and maintenance of MSNs for this cellular HD model;
Specific Aim 3. We will determine if factors that promote MSN differentiation or maintenance ameliorate HD
phenotypes in mouse models of the disease. Therapeutic targets will be identified and new treatments for HD
will be explored.

## Key facts

- **NIH application ID:** 10011887
- **Project number:** 5R01NS100529-05
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Lisa M Ellerby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $614,226
- **Award type:** 5
- **Project period:** 2016-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011887

## Citation

> US National Institutes of Health, RePORTER application 10011887, Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem Cells (5R01NS100529-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10011887. Licensed CC0.

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