# Development of allele-specific protein-based therapeutic targeting the pathogenic RNA associated with Spinocerebellar ataxia type 3

> **NIH NIH R44** · ENZERNA BIOSCIENCES, LLC · 2022 · $259,142

## Abstract

ABSTRACT
 Polyglutamine (polyQ) diseases represent one of the more common classes of inherited neurodegenerative
diseases. They are caused by expanded CAG repeats that encode abnormally long glutamine stretches in the
disease proteins. Of the nine known polyQ disorders, Spinocerebellar Ataxia type 3 (SCA3), also known as
Machado-Joseph disease (MJD), is the second most common in the US and the most common in the world.
SCA3 is also the most common dominantly inherited ataxia with degeneration primarily affecting the cerebellum,
brainstem, substantia nigra, thalamus and spinal cord. In SCA3, a CAG repeat within the ATXN3 coding
sequences which normally harbors 12 to 44 CAGs is expanded to 60 to 87 triplets. Currently, only palliative
therapeutics to manage symptoms are available. Therapeutic strategies directly targeting expanded SCA3
mRNAs, such as antisense oligonucleotides (ASO), have produced promising results. The recent halt of two
ASO-based therapeutics in clinical trials for the polyQ disorder, Huntington’s Disease demonstrates, the need
for the development and assessment of a diverse set of treatment modalities.
 In this proposal, we propose to use our Artificial SiteSpecific RNA Endonucleases (ASREs) technology to
design CAG repeat specific RNA endonuclease to destroy expanded pathogenic SCA3 RNAs. ASREs contain
RNA binding domains isolated from PUF proteins, which consist of a series of ~36 amino acid modules that
recognize one specific ribonucleotide. In proof-of-concept studies, we have designed ASREs hat appear to
preferentially target the expanded ATXN3 RNA. In this FastTrack proposal, we will seek to further increase
therapeutic options for SCA3. In Phase I, we seek to assess the feasibility of engineering ASREs that can target
two SNPs, located within the coding sequences, that frequently co-segregate the expanded allele to take
advantage of the observations that ASO based therapeutics to these SNPs show promising efficacy results.
These studies will enable Enzerna to build a portfolio of gene therapeutics that provide the possibility of precision
medicine approaches appropriate for the specific SCA3 disease allele carried by the patient. In Phase, II, in
vitro and in vivo studies will be conducted to assess rescue of SCA3-associated phenotypic anomalies after
AAV-mediated delivery of the candidate ASRE therapeutics.
 In the long term, combined with gene delivery vectors, ASREs provide a new strategy for selective
degradation of pathogenic ATXN3 transcripts. By targeting the underlying basis of SCA3 (MJD), ASREs provide
the possibility of a preventative and/or curative therapy for this incurable class of human diseases.
.

## Key facts

- **NIH application ID:** 10552829
- **Project number:** 1R44NS127711-01A1
- **Recipient organization:** ENZERNA BIOSCIENCES, LLC
- **Principal Investigator:** JOSEPH C. RUIZ
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $259,142
- **Award type:** 1
- **Project period:** 2022-08-19 → 2024-08-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552829

## Citation

> US National Institutes of Health, RePORTER application 10552829, Development of allele-specific protein-based therapeutic targeting the pathogenic RNA associated with Spinocerebellar ataxia type 3 (1R44NS127711-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10552829. Licensed CC0.

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