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A Micro-RNA Approach for the Treatment of Spinocerebellar Ataxia Type 6 (SCA6)

Published:
Lead Inventor: Christopher Gomez
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SUMMARY

  • Spinocerebellar ataxia type 6 (SCA6) is a rare, dominantly inherited disease that causes Purkinje cell degradation and results in: loss of coordination, tremors, and uncoordinated muscle movement. Current therapies only mitigate symptoms and do not address the underlying pathophysiology responsible for disease progression.
  • It is known that individuals with SCA6 have an expanded PolyQ tract in the CACNA1A gene (Q4-Q17 to Q19-Q33), but it was previously inconclusive as to how this abnormality impacts translation of the gene to the product ion channel a1A. The inventors discovered that the CACNA1A gene is bicistronic assoiciated with an IRES and encodes a transcription factor (a1ACT). The Poly Q variant of a1ACT promotes Purkinje cell degradation, while the canonical variant is essential for Purkinje cell function. 
  • The invention is a microRNA (3191), that blocks the IRES-mediated translation of the pathogenic Poly Q variant of the a1ACT transcription factor, without impacting translation of the the associated a1A ion channel. The microRNA therefore has the potential to treat SCA6 with minimal off-target effects.
  • In in vivo proof of concept experiments, the inventors delivered miRNA 3191 via AAV9 to mice models of SCA6 and demonstrated that the therapeutic protected the mice from Purkinje cell degradation and motor defects associated with the ataxia.

 

FIGURE

SCA6-a1ACT reporter mice were either treated with an AAV with GFP mRNA and miRNA3191 (black), miRNA3191 alone (red), or endogenous miRNA(blue). (A) a1ACT expression was monitored via FLAG tag fluorescence in various areas of the mouse brain and was shown to decline for mice treated with miRNA3191+ AAVs. (B) Mouse movement behavior was monitored at 4 weeks of age. Mice treated with miRNA3191+ AAVS travel farther distances, indicative of reduced SCA6 associated symptoms.

 

 

ADVANTAGES

ADVANTAGES

  • SCA6 disease modifying therapeutic
  • Fulfills unmet treatment need
  • Highly specific mechanism of action (minimizes side effects)
  • Developed associated mouse model for preclinical validation

 

APPLICATIONS

  • Spinocerebellar ataxia type 6 gene therapy (AAV delivered)  

 

PUBLICATIONS

 

 

 

  • US: 10,017,765 Additional patent pending