# Characterization of small molecules that lower mutant huntingtin protein as potential therapeutics for Huntington’s disease

> **NIH NIH R43** · ORIGAMI THERAPEUTICS, INC. · 2024 · $107,065

## Abstract

SUMMARY
Huntington’s disease (HD) is an autosomal dominant, progressive and fatal neurodegenerative disease that
effects 200,000 people worldwide. Despite discovery of the gene more than 25 years ago and more than 150
clinical trials, there is still no effective treatment for HD. The development of any therapy that slows, halts, or
prevents disease would have a major impact on the patients and their families. HD is caused by the expansion
of a CAG repeat in the huntingtin gene (HTT), resulting in an expanded stretch of glutamines in the huntingtin
protein. Normal huntingtin protein (HTT) is essential throughout the body and brain to regulate cell physiology
including synaptic transmission and neuroprotection, cell division and differentiation, gene transcription and the
DNA damage response. In patients with HD, the expanded polyglutamine tract causes mutant HTT (mHTT) to
fold abnormally, resulting in aberrant post-translational modifications and cleavage to generate toxic mHTT
fragments. The N-terminal mHTT fragments form oligomers that interact with many cellular proteins, disrupting
cell function, resulting in increased levels of mHTT and causing mHTT inclusions. Substantial neuronal
dysfunction and death occur in striatal medium spiny neurons (MSNs) and the cerebral cortex. Experimental
procedures that lower mHTT have reversed disease symptoms in animal models of HD. However, clinical
translation of this mechanism of action has stalled and is, in part, hypothesized to be due to nonselective lowering
of both the essential HTT as well as mHTT. In addition, some of the drug candidates in clinical trials target the
brain exclusively, use therapeutic modalities that require invasive delivery systems and leave the rest of the body
untreated. Therefore, an orally delivered, systemically distributed, brain-penetrant therapeutic that selectively
eliminates toxic mHTT while sparing the functional forms of HTT to support normal physiology could offer an
effective treatment for all HD patients. By applying its expertise in screening, Origami Therapeutics (OT) has
identified a chemical scaffold, represented by OR1-113, that prevents mHTT aggregation, and selectively lowers
mHTT levels in cell-based assays by enhancing degradation through an autophagy pathway as demonstrated
in HD patient-derived fibroblasts, human HD iPSC-derived medium spiny neurons and in vivo in the cortex and
striatum of the YAC128 mouse model of HD. Twelve analogues of ORI-113 have been designed. The efficacy
and drug-like properties of OR1-113 and 12 analogues will be compared in HD patient iPSC-derived MSNs and
in vitro absorption, distribution, metabolism, and excretion studies will provide insight regarding the metabolism
and potential interactions of the drug compounds (Aim 1). Pharmacokinetic (PK) and brain exposure profiles of
four lead compounds selected from Aim 1 will be determined in mice for oral availability (Aim 2). The top two
ranked leads will be evaluated in a combine...

## Key facts

- **NIH application ID:** 10929461
- **Project number:** 5R43NS127716-02
- **Recipient organization:** ORIGAMI THERAPEUTICS, INC.
- **Principal Investigator:** Beth J Hoffman
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $107,065
- **Award type:** 5
- **Project period:** 2023-09-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929461

## Citation

> US National Institutes of Health, RePORTER application 10929461, Characterization of small molecules that lower mutant huntingtin protein as potential therapeutics for Huntington’s disease (5R43NS127716-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10929461. Licensed CC0.

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