Recent advances in the therapeutic development for Huntington disease
Introduction
Huntington disease (HD) is a genetic autosomal dominant neurodegenerative condition caused by a CAG trinucleotide expansion in exon 1 of the huntingtin gene (HTT) [1]. The clinical disease typically presents in a variable combination of 1) a complex movement disorder, 2) cognitive problems predominantly of the dysexecutive type and 3) behavioural problems ranging from apathy, irritability to depression. There is no cure for HD, and the disease progresses relentlessly with an expected survival of 15–20 years after the initial symptom presentation [2]. Variations in the clinical presentation of HD include Juvenile HD with onset before age 21 and a distinct clinical phenotype [3], and late-onset HD after age 60 [4].
Section snippets
Overview of current treatment options in HD
Chorea is the only approved treatment indication in HD. Tetrabenazine, an inhibitor of the vesicular monoamine 2 transporter, was the first treatment approved for this indication. More recently, a deuterated version of tetrabenazine (SD-809) was approved by the US Food and Drug Administration (FDA), following a 12-week randomized, double-blind, placebo-controlled trial suggesting equivalent efficacy and potentially a better tolerability profile relative to tetrabenazine [5]. The claim of better
Emerging experimental therapies for disease modification
The current landscape of therapeutic development in HD holds great promise, namely, for interventions being studied for a disease-modifying effect. The field of HD is shifting away from therapies which rational was based on non-disease specific concepts of neurodegeneration to interventions targeting core upstream disease-specific processes. The most emblematic example of this paradigm shift is the ongoing effort to lower levels of the mutated huntingtin protein (mHTT). Conceptually, the
Compounds assessed for symptomatic treatment in HD
In this section, a selection of clinical trials is presented in detail for their representation of new treatment indications that are presently gaps in the management of HD. A comprehensive list of recent or ongoing clinical trials conducted for symptomatic treatments in HD is provided in Table 2.
Conclusions
In the present review, the reader is guided through a landscape of emerging experimental therapies either with recent or ongoing clinical development in the field of HD. The years to come hold promise for novel, revolutionary therapies aimed at core disease mechanisms, a long-awaited promise for HD patients and families. In addition, the more recent negative results of clinical trials presented in this review are deemed to unlock gates for further therapeutic development as well as for a better
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