Elsevier

Parkinsonism & Related Disorders

Volume 59, February 2019, Pages 125-130
Parkinsonism & Related Disorders

Recent advances in the therapeutic development for Huntington disease

https://doi.org/10.1016/j.parkreldis.2018.12.003Get rights and content

Highlights

  • The therapeutic development in Huntington disease is rich and promising.

  • Disease-specific therapies are being developed for the first time.

  • New symptomatic treatment indications have been recently evaluated.

Abstract

Introduction

Huntington disease (HD) is a rare genetic neurodegenerative condition. The availability of a genetic diagnosis makes HD an attractive model for the development of therapies that can delay or, at best, halt the progression of neurodegenerative conditions. Tetrabenazine and deutetrabenazine are the only treatment options with a formal indication (chorea) for this patient population.

Methods

Literature review on HD and clinical trials using the medical databases Pubmed, Web of Science, and clinical trial registries. Recent clinical trials conducted with the goal of disease-modification or new symptomatic treatment indications were included. Non-pharmacological interventions were excluded.

Results

Therapeutic approaches aiming at disease-modification include huntingtin-lowering strategies, the modulation of huntingtin homeostasis and neuroinflammation. Huntingtin-lowering strategies are of particular interest by targeting the mRNA of the huntingtin (HTT) gene at the core of HD biology. Antisense oligonucleotides (ASO) are the only huntingtin-lowering strategies in clinical development. The initial results suggest that the first non-allele specific ASO was safe and associated with a reduction in the levels of mutated huntingtin protein (mHTT). Other clinical trials for disease-modification in HD have generated negative results or are ongoing. Assays to measure CSF mHTT and brain nuclear imaging specific to HD can support the rational development of these therapies. Novel symptomatic treatment indications explored in clinical trials include motor disability, irritability and apathy.

Conclusions

The years ahead are promising for novel and revolutionary therapies aimed at core disease mechanisms in HD. Clinical research platforms such as Enroll-HD are expected to potentiate the conduction of clinical trials in HD.

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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