Biologics: Targets & Therapy (Sep 2022)
Emerging Therapies for Huntington’s Disease – Focus on N-Terminal Huntingtin and Huntingtin Exon 1
Abstract
M Leontien van der Bent, Melvin M Evers, Astrid Vallès uniQure biopharma B.V., Department of Research and Development, Amsterdam, the NetherlandsCorrespondence: Astrid Vallès, uniQure biopharma B.V, Postbus 22506, Amsterdam, 1100 DA, the Netherlands, Tel +31 20 240 6000, Email [email protected]: Huntington’s disease is a devastating heritable neurodegenerative disorder that is caused by the presence of a trinucleotide CAG repeat expansion in the Huntingtin gene, leading to a polyglutamine tract in the protein. Various mechanisms lead to the production of N-terminal Huntingtin protein fragments, which are reportedly more toxic than the full-length protein. In this review, we summarize the current knowledge on the production and toxicity of N-terminal Huntingtin protein fragments. Further, we expand on various therapeutic strategies targeting N-terminal Huntingtin on the protein, RNA and DNA level. Finally, we compare the therapeutic approaches that are clinically most advanced, including those that do not target N-terminal Huntingtin, discussing differences in mode of action and translational applicability.Keywords: Huntingtin, N-terminal fragments, proteolysis, aberrant splicing, exon1 fragment, Huntington’s disease therapeutics
