# Endogenous regulation of  huntingtin expression as a therapeutic target for Huntington's disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $470,932

## Abstract

Summary.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by
relentless progression to death ~20 years after disease onset. HD is caused by an expanded CAG
repeat in exon 1 of the huntingtin (HTT) gene. Disease pathogenesis is largely a result of expression
of the mutant transcript and protein, which have neurotoxic properties. Suppressing the expression of
the mutant allele is therefore a promising therapeutic approach, thus far pursued with antibody,
oligonucleotide and siRNA strategies. As with any knockdown approach, especially in the CNS,
problems of delivery, reversibility, and off-target effects using these methods remain problematic.
Surprisingly, relatively little is known about the regulation of the HD locus, and in particular on the
mechanisms that regulate HTT expression. We have recently discovered a gene on the strand
antisense to HTT at the HD locus, which we have termed huntingtin antisense (HTT-AS). We have
demonstrated that increasing expression of HTT-AS decreases expression of HTT, and that HTT-AS
expression can be manipulated using small molecules. We hypothesize that HTT-AS itself, and the
components that regulate its expression and interaction with HTT, will provide novel therapeutic targets
for suppression of HTT expression and hence treatment of HD. A corollary to this hypothesis is that
a better understanding of the HD locus, in this case the role of HTT-AS, will be critical in the
interpretation of any HTT suppression strategy. We will test this hypothesis with a series of experiments
organized into three specific aims, each built on compelling preliminary data. In Aim 1, we will
determine if additional HTT-AS exons, splice variants, and promoters exist, determine the effect of
repeat expansion on HTT-AS expression, and identify protein factors that regulate HTT-AS promoter
activity. In Aim 2, we will determine the mechanisms by which HTT-AS suppresses HTT, including the
quantitative effect of different HTT-AS transcripts on the suppression of HTT, and the role of chromatin
remodeling on HTT expression. In Aim 3, we will collaborate with NCATS and CHDI to perform a large
scale high throughput screen to find and characterize compounds that decrease expression of HTT by
specifically increasing expression of HTT-AS. Selected compounds will be validated in cell and mouse
models.

## Key facts

- **NIH application ID:** 9963423
- **Project number:** 5R01NS100783-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** RUSSELL L MARGOLIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $470,932
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963423

## Citation

> US National Institutes of Health, RePORTER application 9963423, Endogenous regulation of  huntingtin expression as a therapeutic target for Huntington's disease (5R01NS100783-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963423. Licensed CC0.

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