Can MSH3 lowering stop HTT repeat expansion in its CAG tract?

Abstract

Huntington’s disease (HD) is a neurodegenerative repeat expansion disorder caused by an expansion of the CAG trinucleotide repeat present in exon 1 of the huntingtin (HTT) gene. The expanded repeat exhibits instability in somatic tissues, resulting in an inexorable increase in length over the HD gene carrier’s lifetime. Although the length of the expanded CAG repeat is the strongest predictor of age at onset and progression, potential genetic modifiers have also been identified. 1 Moss D.J.H. Pardiñas A.F. Langbehn D. Lo K. Leavitt B.R. Roos R. Durr A. Mead S. TRACK-HD investigators REGISTRY investigators et al. Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study. Lancet Neurol. 2017; 16: 701-711 Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar ,2 Genetic Modifiers of Huntington’s Disease GeM-HD Consortium Lee J.-M. Correia K. Loupe J. Kim K.-H. Barker D. Hong E.P. Chao M.J. Long J.D. Lucente D. et al. CAG repeat not polyglutamine length determines timing of huntington’s disease onset. Cell. 2019; 178: 887-900.e14 Abstract Full Text Full Text PDF Scopus (183) Google Scholar Many of these modifiers are within DNA repair genes and have been implicated in repeat expansion, including the mismatch repair protein MSH3. The process of somatic repeat expansion in the brain appears to be a major factor in driving disease progression, leading to production of more toxic HTT protein species. As a monogenic disease, many genetic therapeutic approaches past and present aim to ameliorate the effects of the mutant HTT protein by lowering its levels. In this issue of Molecular Therapy, O’Reilly and colleagues 3 O'Reilly D. Belgrad J. Ferguson C. Summers A. Sapp E. McHugh C. Mathews E. Boudi A. Buchwald J. Ly S. et al. Di-valent siRNA mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington’s disease. Mol. Ther. 2023; https://doi.org/10.1016/j.ymthe.2023.05.006 Abstract Full Text Full Text PDF Google Scholar demonstrate the potential of an alternative therapeutic intervention to slow the expansion of the CAG repeat by targeting MSH3. They achieve suppression of somatic expansion in two different but complementary HD mouse models by instead lowering the expression of MSH3, using a nucleic acid therapeutic modality established previously by the Khvorova group, the di-valent siRNA (di-siRNA). 4 Alterman J.F. Godinho B.M.D.C. Hassler M.R. Ferguson C.M. Echeverria D. Sapp E. Haraszti R.A. Coles A.H. Conroy F. Miller R. et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat. Biotechnol. 2019; 37: 884-894 Crossref PubMed Scopus (81) Google Scholar