Huntington disease (HD) is an inherited neurodegenerative disease characterized by a clinical triad of motor, cognitive, and psychiatric symptoms. Common motor symptoms include chorea, dystonia, and incoordination. The cognitive symptoms are primarily subcortical, which results in a dysexecutive syndrome. Common neuropsychiatric symptoms include apathy, anosognosia, irritability, impulsivity, depression, and anxiety.1
The autosomal dominant inheritance pattern of HD has been known for decades. The specific mutation, however, was described over 26 years ago and is a highly penetrant CAG trinucleotide repeat expansion in the huntingtin (HTT) gene (chromosome 4 (4p16.3)]).2 The CAG repeat expansion in exon 1 is translated into an expanded polyglutamine resulting in a mutant HTT protein (mHTT). Ubiquitous at the tissue and subcellular level, wild-type HTT (wtHTT) has numerous functions, not all of which are understood, including tissue maintenance, cell morphology and survival, and control of organelle and vesicle transport. In the nucleus, HTT may act as a scaffold for transcriptional complexes. Of note, the HTT gene is thought to be necessary for embryonic development.3
The identification of the huntingtin gene, previously known as interesting transcript 15 (IT15) has been a major milestone in HD research and several disease-modifying therapies (DMTs) have been studied since its discovery, although none have yet proven efficacy or been approved.4 Various compounds have been tested, including novel approaches targeting immune dysregulation in HD, mitochondrial-based protective strategies, and gene-modifying technologies (Table).
Current treatments are purely symptomatic, aimed at improving function and quality of life for people with HD. Pharmacologic options for the motor symptoms include neuroleptics, gabaergics, and antiglutaminergics, all of which are used off-label. The vesicular monoamine transporter 2 (VMAT2) inhibitors, tetrabenazine and deutetrabenazine, are the only 2 medications currently approved by the Food and Drug Administration (FDA) for the treatment of chorea in HD. Antidepressants, neuroleptics, and mood stabilizers are often used to treat neuropsychiatric symptoms. Interdisciplinary, nonpharmacologic treatments are also important, including physical, occupational, and speech therapy, psychotherapy, genetic counseling, nutrition and social work services.4
Investigational Disease-Modifying Treatments
Initial attempts to develop DMTs for HD focused on cellular mechanisms associated with neuronal death, such as glutamate-mediated excitotoxicity, and apoptosis. Subsequently, other neurodegenerative mechanisms were targeted, including inflammatory and immune mechanisms, oxidative stress, and mitochondrial dysfunction. Despite promising results in preclinical studies, none of these have yet demonstrated efficacy as DMTs for HD. Several factors may have influenced these disappointing results, including the lack of appropriate clinical and biologic markers for selecting participants and tracking disease progression and modification. In addition, the power of the studies and clinical scales used as primary endpoints may not have been sensitive enough to detect changes in disease progression. More recently, strategies have shifted from nondisease specific neurodegeneration to interventions targeting core upstream disease-specific processes.5 This revolutionary change has been made possible by rapid advances in gene-modifying technology. Current and future trials are focused on reducing the amount of mHTT (Figure).
Fig. 1: Strategies for Lowering Mutant Huntingtin Levels. Different approaches for lowering mutant huntingtin (mHTT) include using clustered regularly interspaced short palindromic repeats (CRISPR)‑Cas9 to edit DNA so mHTT is not transcribed, antisense oligonucleotides (ASOs) to reduce production of mRNA during processing (splicing) of pre-mRNA, microscopic or small interfering RNA (miRNA or siRNA) to reduce production of mHTT protein during mRNA translation, and protein modulation to reduce aggregation or increase clearance.
Lowering Mutant Huntingtin Levels
Lowering mHTT levels is among the most promising strategies for developing DMTs for HD. These strategies are focused on inhibiting messenger RNA (mRNA) synthesis by blocking transcription with zinc finger motif proteins, avoiding posttranscriptional processing to increase mRNA degradation with antisense oligonucleotides (ASOs), and inhibiting mRNA translation with small interfering RNA (siRNA).5
Antisense Oligonucleotides. Designed to target mRNA, ASOs are synthetic, short, single-stranded DNA sequences that form a hybridized complex with specific mRNAs causing them to be degraded through an RNAse-H1 mechanism. The first human clinical trial with ASO therapy for lowering HTT evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of tominersen administered intrathecally to 46 participants with early manifest HD at 4-week intervals for 13 weeks. Tominersen is nonallele-specific and thus targets both wtHTT and mHTT. Preliminary results suggest that tominersen is safe, and well tolerated. At the 90-mg and 120-mg doses, tominersen was associated with an approximately 40% reduction of mHTT levels in cerebrospinal fluid (CSF), which may correspond to a 55% to 85% reduction in cortical mHTT levels. There was also a correlation between reduced CSF mHTT levels and improved composite Unified Huntington Disease Rating Scale (cUHDRS) scores.6
There are 2 open-label extensionsa underway for participants who have previously received tominersen and a phase 3 double-blind placebo-controlled interventional trial evaluating safety and efficacy in individuals with manifest HD along with a natural history study. The primary outcome measure for the pivotal trial is the total functional capacity (TFC) in the US and the cUHDRS outside the US. Secondary outcomes include additional components of the UHDRS, including cognitive and behavioral assessments, the clinical global impression score, adverse events, pharmacokinetic markers, CSF mHTT, neurofilament (NfL) levels, and brain volume on MRI.
Tominersen has demonstrated reduction in CSF HTT levels, and efficacy of the treatment is under investigation. It is unclear, however, if residual mHTT levels and lowering both wtHTT and mHTT levels in the CSF are clinically relevant. HTT is a highly conserved protein with several important cellular functions,3 it is unclear if wtHTT reduction has long-term safety. In this regard, the use of an allele-specific ASO is an interesting alternative. There are 2 randomized double-blind placebo-controlled phase 1a/2b trials studying safety, tolerability, pharmacokinetics, and pharmacodynamics of intrathecally administered allele-specific ASOs in people with early manifest HD (Table). Allele specificity has been achieved by developing stereopure ASOs directed at specific single nucleotide polymorphisms (SNPs). Both trials are enrolling participants with specific HTT SNPs on the same allele as the pathogenic CAG expansion.
Small Interfering RNAs. The siRNA and artificial microRNA (miRNA) neutralize mRNA molecules to inhibiting mRNA translation, a process known as RNA interference (RNAi).7,8 Using the adeno-associated viral (AAV) vector to deliver an siRNA targeting mHTT mRNA in a mouse model of HD, more than 80% of the cells in the striatum were successfully transduced (ie, expressed the siRNA). Of note, there were also significant improvements in HD-associated behavioral deficits and the reduction of striatal HTT aggregates in the transfected mice.9 A cholesterol-conjugated siRNA targeting HTT (cc-siRNA-HTT) ameliorated HD-related neuropathology and motor deficits in a different mouse model.8 An artificial miRNA delivered via the AAV vector to a sheep model of HD also reduced 50% to 80% of HTT mRNA and protein in the striatum and prevented subsequent neuron loss at 1 and 6 months after injection. The sheep model results show that effective silencing of mHTT by AAV-delivered artificial miRNA can be achieved and sustained in a large-animal brain.10 Another mouse model injected with an AAV-delivered microRNA (miRNA) for human HTT mRNA selectively knocks down expression and is most effectively delivered to the putamen and thalamus with MRI-guided injection and reduced HTT levels in deep brain tissues, such as the caudate, putamen, and thalamus, in addition to the cortex. This treatment was well tolerated by the animals for up to 5 weeks and phase 1 clinical trials in humans with HD are expected to begin soon.11
Similarly, an engineered miRNA delivered via AAV vector serotype 5 (AAV5-miHTT) in a single intrastriatal injection into a minipig model of HD resulted in a strong, widespread and sustained (up to 12 months) reduction of mHTT levels and a phase 1 trial of this agent in humans with HD is also beginning.
Genome Editing. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)9 system has emerged as a promising option because of allele-specificity and potency. The CRISPR/Cas9 technology was used in fibroblasts of an HD patient to delete the promoter regions, transcription start site, and the CAG mutation expansion of the mHTT gene. Complete inactivation of the mutant allele occurred without effects on the normal allele.12 The CRISPR/Cas9 method has also been tested in an HD rodent model and efficiently depleted HTT and reversed the HD-associated neuropathology and behavioral phenotypes. Decreased mHTT expression did not affect cell viability, but alleviated motor deficits.13 Despite the positive results in preclinical studies, however, several issues must be addressed before bringing CRISPR/Cas9 technologies into humans, including that it is irreversible with ethical concerns regarding germline alteration and that there are delivery problems with viral vectors and concerns about the possible immunogenicity of bacterial proteins.14
Huntingtin Protein Modulation
Strategies for HTT protein modulation include clearance and inhibition of protein aggregation. Excessive metal concentrations induce mHTT aggregation and promote formation of reactive oxygen species (ROS). Therefore, it has been hypothesized that 8-hydroxyquinoline transition metal ligand, which redistributes metals (eg, copper, zinc, and iron) from locations where they are abundant to subcellular locations where they might be deficient, could attenuate mHTT effects by inhibiting metal-induced aggregation.15 In preclinical studies in Caenorhabditis elegans and mouse models of HD, 8-hydroxyquinoline transition metal ligand was effective in ameliorating the HD phenotype.16 In a 26-week phase 2 randomized double-blind placebo-controlled clinical trial, 109 participants with HD had significant improvement in cognition (Trail Making Test Part B) with a 250-mg dose, but no effects in other domains were seen compared with the 100-mg dose or placebo. This isolated finding was thought to be of limited clinical relevance.15 Although the treatment was considered safe and well tolerated, the FDA issued a partial clinical hold because of safety concerns for the 250-mg dose and required more neurotoxicity data. There have been no recent updates.
Selisistat has been studied for promotion of HTT protein clearance. Selisistat is an inhibitor of the silent information regulator T1 (SirT1), which is a member of the sirtuin deacetylase family that can remove acetyl groups from mHTT. Inhibition of SirT1 alleviated pathology in animal and cell models of HD.17 Clinical trials of selisistat demonstrated that it is safe and well tolerated but failed to show efficacy.18,19 Another trial has been registered that will assess selisistat in fasted vs fed conditions (ie, the effect of food on the pharmacokinetics of selisistat in patients with HD). The study was designed to explore potential biomarkers for use in subsequent phase 2/3 studies, but no results have been published to date. There are no phase 3 trials planned; further development appears to be on hold.
Immune dysregulation and mitochondrial dysfunction are regarded as important contributors to neurodegeneration in HD and have been targets for HD-modifying therapies.
Immunomodulatory Agents. The immunomodulatory strategies for HD include laquinimod, an immunomodulatory drug originally studied for the treatment of relapsing-remitting multiple sclerosis; minocycline, a second-generation tetracycline that has been in therapeutic use for over 30 years; and pepinemab, an investigational antibody to semaphorin 4D (SEM4D). Neuroprotective and HD-ameliorating effects of laquinimod in preclinical studies20-22 motivated clinical trials in participants with HD. In randomized placebo-controlled double-blind trials, neither 12 weeks of laquinimod or 8 weeks of minocycline vs placebo showed efficacy as measured by change in the UHDRS or cognitive test scores. The laquinimod treatment, however, was correlated with a significant reduction in caudate and whole-brain atrophy that was most evident in people with early manifest HD. At this time, it is unclear how a positive MRI-based secondary outcome in the setting of a negative clinical primary outcome should be interpreted. It is possible that laquinimod would be more efficient if it were initiated years (or even decades) before disease onset, thus preventing neurodegeneration. Regarding minocycline, the short-period treatment could explain the lack of efficacy; however, no results were seen in another trial of 18 months of minocycline treatment.23
Pepinemab is an antibody against SEM4D thought to decrease central nervous system inflammation, increase neuronal outgrowth, and enhance oligodendrocyte maturation. Pepinemab is being evaluated in a phase 2 multicenter randomized double-blind placebo-controlled study assessing safety, tolerability, pharmacokinetics, and efficacy in participants with prodromal or early manifest HD.
Mitochondrial-Based Agents. Several clinical trials have evaluated antioxidant treatment with coenzyme Q10 (CoQ10) and creatinine as potential DMTs for HD. Although both CoQ10 and creatinine were generally safe and well tolerated, neither slowed functional decline in HD and the trials were terminated based on interim analyses.24-27 The effects of ethyl-eicosapentaenoic acid (ethyl-EPA) in HD have also been tested but showed no beneficial effects in measures of motor function, global functioning cognition, or global impression.28 Latrepirdine (dimebon) was also tested as a modulator of mitochondrial dysfunction in HD. Treatment with latrepirdine vs placebo correlated with a discrete but significant improvement in the Mini-Mental State Examination (MMSE), but not other cognitive outcome measures in a phase 2 trial.29 In a subsequent multicenter 26-week randomized double-blind placebo-controlled study, no improvement in cognition or global function compared to baseline was seen in participants with HD who had cognitive impairments,30 and an open-label extension was terminated.
Based on promising data from preclinical studies, multiple clinical trials have been conducted. targeting different aspects of HD pathology, including mHTT aggregation, neurodegeneration, immune/inflammatory mechanisms, glutamate-mediated excitotoxicity, the dopamine pathway, and mitochondrial dysfunction. None have yet been successful in identifying a drug with proven efficacy to modify HD progression; however, pending results may be positive. Several factors might influence the previous disappointing results, including underpowered studies and the lack of appropriate clinical and biological markers capable of tracking disease modification. The clinical scales currently used as primary endpoints might not be sensitive enough at detecting signs and symptoms of disease progression. New innovative tools to objectively assess disease signs and symptoms and the development of neuroimaging-based or biological fluid-based markers of disease progression will be imperative to the success of clinical trials in HD.
The recent advances in therapeutic strategies promise an exciting era for clinical trials in HD. Current and future trials are focused on lowering mHTT by targeting mHTT production, aggregation, misfolding, and removal. The ASOs are the furthest along in clinical development in the realm of huntingtin-lowering strategies; however, many questions remain, particularly long-term safety and the effect of decreasing wtHTT levels. The results of studies using CRISPR/Cas9 technologies in preclinical models of HD are very encouraging, yet these techniques are distant from use in humans. In summary, the landscape is changing for many inherited conditions due to recent technological advances in gene modifying approaches. The future for HD disease-modifying research is promising, although with continued discovery, new questions and challenges emerge.
a. See table for NCT identifiers of all clinical trials mentioned without published results
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NPR, GDC, ALT report no disclosures
EFS receives research funding from the CHDI Foundation, Huntington's Disease Society of America, Cures within Reach, Vaccinex, and Uniqure; has been a paid consultant for WebMD/Medscape; and is a paid dvisory board member for Amneal