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Development of an AAV-Based MicroRNA Gene Therapy to Treat Machado-Joseph Disease

Raygene Martier1,2, Marina Sogorb-Gonzalez1,2, Janice Stricker-Shaver3

  • 1Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands.

Molecular Therapy. Methods & Clinical Development
|December 13, 2019
PubMed

Insights

Researchers developed artificial microRNAs (miATXN3) to silence the ATXN3 gene, the cause of Spinocerebellar ataxia type 3 (SCA3). Promising results in vitro and in vivo support further investigation for SCA3 treatment.

Area of Science:

  • Neurogenetics
  • Molecular Biology
  • Gene Therapy

Background:

  • Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder.
  • It is caused by a CAG repeat expansion in the ATXN3 gene, leading to toxic polyglutamine protein accumulation and neuronal degeneration.
  • Current therapeutic strategies for SCA3 are limited, necessitating novel approaches targeting the underlying genetic cause.

Purpose of the Study:

  • To investigate the efficacy and safety of a non-allele-specific ATXN3 silencing approach using artificial microRNAs (miATXN3).
  • To evaluate the potential of AAV5-mediated delivery of miATXN3 for treating Spinocerebellar ataxia type 3.
  • To assess the biodistribution and target engagement of AAV5-miATXN3 in relevant preclinical models.

Main Methods:

  • Engineered artificial microRNAs (miATXN3) targeting various regions of the ATXN3 gene.
  • In vitro screening using a luciferase reporter assay to assess silencing efficacy.
  • Testing in induced pluripotent stem cell (iPSC)-derived neurons and a SCA3 knockin mouse model for target engagement and off-target effects.
  • Small RNA sequencing to analyze guide and passenger strand processing.
  • Assessment of AAV5-miATXN3 delivery and transduction in a minipig model.

Main Results:

  • Identified potent miATXN3 candidates demonstrating significant reduction of ATXN3 mRNA and protein levels.
  • Small RNA sequencing confirmed efficient guide strand processing with minimal passenger strand production.
  • No evidence of significant off-target gene alterations was detected using predictive methods.
  • Intrathecal delivery of AAV5 successfully transduced key brain regions affected in SCA3 patients in a large animal model.

Conclusions:

  • Artificial microRNAs targeting ATXN3 show strong potential for silencing the disease-causing gene in Spinocerebellar ataxia type 3.
  • AAV5-mediated delivery of miATXN3 is a viable strategy for targeting affected brain areas.
  • Preclinical data provide a strong foundation for advancing AAV5-miATXN3 towards clinical investigation for SCA3.

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