Ataxia research 4/23

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 I realize it has been a little quiet on the science and research front, but I hope those of you who attended the NAF conference enjoyed it and saw some progress. I just did a PubMed search on SCA6 and came across this summary of gene suppression studies in SCA mouse models. 



They chose Dr. Gomez's manuscript to review (...because it is the best...Pastor, P.D.H.; Du, X.; Fazal, S.; Davies, A.N.; Gomez, C.M. Targeting the CACNA1A IRES as a Treatment for Spinocerebellar Ataxia Type 6. Cerebellum 2018, 17, 72–77.) and wrote this:

The CACNA1A gene encodes both the α1A protein (pore-forming protein) and the α1ACT protein (transcription factor involved in cerebellar development) [39]. A polyQ-expanded α1ACT protein is responsible for SCA6, with the α1A protein being essential to life. Therefore, the selective silencing of α1ACT would be the desirable approach, in contrast to full CACNA1A gene silencing [39]. On the basis that α1ACT is translated with an internal ribosome entry site (IRES), in contrast to α1A cap-dependent translation, Pastor et al. studied an miRNA that silenced these sequences within the CACNA1A IRES region. The authors tested miRNA in a hyperacute SCA6 mouse model [39]. Regarding suppression efficacy, the miRNA-treated group showed lower mutant α1ACT protein levels than the control while keeping α1A levels similar to those of the control. When assessing neuropathological features, the authors identified a protective role in cerebellar molecular layer thinning, decreased dendritic tree density and a decreased number of Purkinje cells. In addition, motor deficits were improved in the treated group when compared with the control; better performance in the rotarod test, greater distances in the open-field assay and improved gait instability in all four limbs were observed [39].

I'm hoping this terrific foundational work continues to progress in the Gomez lab and elsewhere, including pharmaceutical companies, and eventually leads one way or another to an effective interventional therapy.

Best,
Terry

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