Longitudinal Analysis of Somatic Expansion of the HTT Repeat in Blood as a Potential Biomarker of Somatic Instability in Huntingon Disease

Ciosi, M. , Young, R., Kwak, S. and Monckton, D. G. (2022) Longitudinal Analysis of Somatic Expansion of the HTT Repeat in Blood as a Potential Biomarker of Somatic Instability in Huntingon Disease. EHDN2022 Plenary Meeting - D: Wet biomarkers, Bologna, Italy, 16-18 September 2022. (doi: 10.1136/jnnp-2022-ehdn.57)

Abstract

Because it is associated with earlier age at onset, faster progression, and higher severity of Huntington disease (HD), somatic expansion of the HTT repeat is a therapeutic target in HD. Because the cells mostly affected by HD in the brain are not readily accessible, a peripheral biomarker of somatic expansion of the HTT repeat would be a useful tool for preclinical and clinical studies aiming at slowing down the rate for somatic expansions. To determine whether somatic expansion of the HTT CAG repeat in blood is a potential peripheral biomarker, we quantified HTT somatic expansions in 363 pairs of blood DNA samples collected ~8 years apart from Enroll-HD participants inheriting HTT alleles with 37 to 58 CAGs. Somatic expansions were more frequent in the later sample (p < 2x10-16) overall and remained more frequent for the 30 blood DNA pairs sampled <5 years apart (p = 0.014). Inherited CAG length was the main determinant of the increase in somatic expansions over time. These data indicate that recruiting participants with larger inherited CAG length would allow a smaller cohort size to detect the effect of a drug aimed at reducing somatic expansion. Nonetheless, a preliminary power-analyses indicated that a 3-year long placebo-controlled study of a drug decreasing the rate of somatic expansion in blood by 80% would still require ~150 participants with HTT alleles with >48 CAGs. In conclusion, somatic expansions of the HTT repeat accumulate slowly over time in the blood but are detectable and might be a possible biomarker.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Monckton, Professor Darren and Ciosi, Dr Marc
• Authors: Ciosi, M., Young, R., Kwak, S., and Monckton, D. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences