Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a CAG expansion in the huntingtin (HTT) gene. The first symptoms usually appear in mid-life and progressively worsen over time, including cognitive deficits, mood/behavioral changes, and motor disturbances. In recent years, there have been significant advances in understanding both the cellular pathology and the macroscopic structural brain changes, due to extensive research into the pathophysiology of the disease. However, there remains to be no disease-modifying therapies to delay the onset or slow the progression of HD, despite numerous promising candidates reaching clinical development. Several recent studies have focused on HTT lowering using antisense oligonucleotides (ASOs), however, these studies were unable to meet primary endpoints.

Despite this, there is an impressive pipeline of ongoing and upcoming clinical trials aiming to study and refine treatments targeted at the mechanisms driving disease progression and help to provide a better quality of life for patients. In this week’s episode, specialists in the HD field discuss the details of major ongoing studies looking beyond ASOs and give an insight into the implications that their research could have for disease modification and quality of life in HD. The novel agents up for discussion this week are: SAGE-718, a first-in-class oral positive allosteric modulator of NMDAR; pridopidine, an oral sigma-1 receptor agonist; PTC518, an oral RNA splicing modifier; and ANX005, an antibody targeting C1q.

With Aaron Koenig, MD, Sage Therapeutics; Amy-Lee Bredlau, MD, and Brian Beers, BSc, PTC Therapeutics, Inc.; Michael Hayden, MB, ChB, PhD, FRCP, FRSC, Prilenia; Rajeev Kumar, MD, Rocky Mountain Movement Disorders Center; and Ann Morgan, PhD, Annexon Biosciences.