Disease-Modification in Huntington’s Disease: Moving Away from a Single-Target Approach

Abstract

To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss diseasemodifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early onbefore it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processese.g. huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.To date, no disease-modifying therapy exists for Huntington's disease (HD), despite considerable financial investment [1]. Roche pharmaceutics, however, believe that IONIS-HTTRx, a promising new drug candidate, bucks this trend; their milestone payment to IONIS follows completion of a phase 1/2 study of IONIS-HTTRx, an antisense oligonucleotide (ASO), in 46 patients with early-stage HD. The drug was safe and well tolerated, and resulted in dose-dependent reductions in huntingtin protein (HTT) in the cerebrospinal fluid (CSF) of treated participants [2]. Roche anticipate that results of a trial designed to assess clinical efficacy will prove definitive, accelerating FDA-approval of IONIS-HTTRx. Other global leaders in therapeutics -Spark, Voyager, and UniQurehave followed suit with programs targeting the mutant huntingtin (muHTT) mRNA, representing a shift in optimism affording by targeting the 'root cause' of the disease -HTT gene expression [3].Despite a shift in approachfrom downstream to upstream targetsdrug development in HD has adopted a common mentality: searching for a single agent which selectively targets one aspect of HD pathology which would then be universally effective in this condition, regardless of when in the disease course it is administered and in what type of patient [4]. Although such a therapy has proven elusive, the selection of candidate disease-modifying therapies has been grounded in mechanistic insights into HD pathogenesis ( fig. 1). Two potential explanations for such low rates of clinical success have received less consideration, and stem from adopting this mentality. Reason one: combination therapy has been disregardedTo date, it has been assumed that manipulating a single pathogenic process will be sufficient to halt disease progression. Initial attempts at disease modification focussed on counteracting one of the downstream effects of muHTT thought to be a key contributor to neuronal death: mitochondrial dysfunction [5], excitotoxicity [6...

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