Therapy development in Huntington disease: From current strategies to emerging opportunities

Abstract

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration. Research into the mechanistic basis of HD has highlighted a role for bioenergetics abnormalities stemming from mitochondrial dysfunction, and for synaptic defects, including impaired neurotransmission and excitotoxicity. Interference with transcription regulation may underlie the mitochondrial dysfunction. Current therapies for HD are directed at treating symptoms, as there are no disease-modifying therapies. Commonly prescribed drugs for involuntary movement control include tetrabenazine, a potent and selective inhibitor of vesicular monoamine transporter 2 that depletes synaptic monoamines, and olanzapine, an atypical neuroleptic that blocks the dopamine D2 receptor. Various drugs are used to treat non-motor features. The HD therapeutic pipeline is robust, as numerous efforts are underway to identify disease-modifying treatments, with some small compounds and biological agents moving into clinical trials. Especially encouraging are dosage reduction strategies, including antisense oligonucleotides, and molecules directed at transcription dysregulation. Given the depth and breadth of current HD drug development efforts, there is reason to believe that disease-modifying therapies for HD will emerge, and this achievement will have profound implications for the entire neurotherapeutics field.

Guarana (Paullinia cupana) Extract Protects Caenorhabditis elegans Models for Alzheimer Disease and Huntington Disease through Activation of Antioxidant and Protein Degradation Pathways

“…The presence of toxic and insoluble protein aggregates is a common feature of more than 20 neurodegenerative conditions [ 40 – 42 ]. For example, HD is an autosomal-dominant neurodegenerative disorder with earlier onset, as its first symptoms may appear at age 40 [ 43 ]. HD is a polyglutamine disease, genetically characterized by glutamine (CAG) repetitions on huntingtin (Htn) protein gene [ 43 ].…”

Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?

“…It is noteworthy that, when available, the pharmacological treatments for these movement disorders are mainly symptomatic and induce significant side effects (Connolly and Lang, 2014 ; Lerner et al, 2015 ; Dickey and La Spada, 2017 ). Nonetheless, despite its great clinical relevance, the studies evaluating CBD's role on the pharmacotherapy of movement disorders are surprisingly few.…”

A Huntington’s disease (HD) phenocopy leads to the identification of the HD toxin as polyalanine. The relationship between repeat length and age of onset can be reframed as a rate equation and the toxic polyalanine length is found to be about 30.6.

“…It is thought that the repeat sequence "results in production of HTT protein with an expanded polyglutamine tract (polyQ), leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration" (Dickey & La Spada, 2018; however, this is controversial, see Ratovitski et al, 2016;Veitch et al, 2007). Whether this explains the CTG phenocopy is not obvious since they are located next to two different genes (HTT and JPH3) and CTG codes for leucine, not glutamine and glutamine is polar and leucine is non-polar.…”