Abstract
BackgroundHuntington’s disease (HD) is an autosomal dominant neurodegenerative condition caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Optimizing peripheral quantification of huntingtin throughout the course of HD is valuable not only to illuminate the natural history and pathogenesis of disease, but also to detect peripheral effects of drugs in clinical trial.RationaleWe previously demonstrated that mutant HTT (mHTT) was significantly elevated in purified HD patient leukocytes compared with controls and that these levels track disease progression. Our present study investigates whether the same result can be achieved with a simpler and more scalable collection technique that is more suitable for clinical trials.MethodsWe collected whole blood at 133 patient visits in two sample sets and generated peripheral blood mononuclear cells (PBMCs). Levels of mHTT, as well as N-, and C-terminal and mid-region huntingtin were measured in the PBMCs using ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence immunoassay platforms, and we evaluated the relationship between different HTT species, disease stage, and brain atrophy on magnetic resonance imaging.ConclusionsThe assays were sensitive and accurate. We confirm our previous findings that mHTT increases with advancing disease stage in patient PBMCs, this time using a simple collection protocol and scalable assay.
Highlights
Huntington’s disease is a devastating neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the HTT gene, encoding an expanded polyglutamine in the ubiquitously-expressed HTT protein
We previously demonstrated that mutant HTT was significantly elevated in purified Huntington’s disease (HD) patient leukocytes compared with controls and that these levels track disease progression
Levels of Mutant HTT (mHTT), as well as N, and C-terminal and midregion huntingtin were measured in the peripheral blood mononuclear cells (PBMCs) using ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence immunoassay platforms, and we evaluated the relationship between different HTT species, disease stage, and brain atrophy on magnetic resonance imaging
Summary
Huntington’s disease is a devastating neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the HTT gene, encoding an expanded polyglutamine in the ubiquitously-expressed HTT protein. There are currently no disease-modifying therapies for HD but putative therapeutic approaches aim to lower mHTT levels in the CNS [3], with the first trial of a HTT-lowering drug entering Phase 1/ 2a trial in 2015 [10]. Though quantification of mutant and wild-type Huntingtin and their cleaved or truncated species in living Huntington’s disease (HD) patients is challenging, it remains a desirable objective. Huntington’s disease (HD) is an autosomal dominant neurodegenerative condition caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Optimizing peripheral quantification of huntingtin throughout the course of HD is valuable to illuminate the natural history and pathogenesis of disease, and to detect peripheral effects of drugs in clinical trial. We previously demonstrated that mutant HTT (mHTT) was significantly elevated in purified HD patient leukocytes compared with controls and that these levels track disease progression. Our present study investigates whether the same result can be achieved with a simpler and more scalable collection technique that is more suitable for clinical trials
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