SCIENCE TRANSITIONAL MEDICINE

Prudencio M, Garcia-Moreno H, Jansen-West KR, Al-Shaikh RH, Gendron TF, Heckman MG, Spiegel MR, Carlomagno Y, Daughrity LM, Song Y, Dunmore JA, Byron N, Oskarsson B, Nicholson KA, Staff NP, Gorcenco S, Puschmann A, Lemos J, Januário C, LeDoux MS, Friedman JH, Polke J, Labrum R, Shakkottai V, McLoughlin HS, Paulson HL, Konno T, Onodera O, Ikeuchi T, Tada M, Kakita A, Fryer JD, Karremo C, Gomes I, Caviness JN, Pittelkow MR, Aasly J, Pfeiffer RF, Veerappan V, Eggenberger ER, Freeman WD, Huang JF, Uitti RJ, Wierenga KJ, Marin Collazo IV, Tipton PW, van Gerpen JA, van Blitterswijk M, Bu G, Wszolek ZK, Giunti P and Petrucelli L

Sci Transl Med. 2020 Oct 21;12(566):eabb7086

DOI: 10.1126/scitranslmed.abb7086

Abstract

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.