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International Parkinson and Movement Disorder Society
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Huntington’s disease: Updates on genetics, therapeutics, and a new cohort

Date: August 2022  
Prepared by SIC Member: Jee-Young Lee, MD, PhD  
Authors: Edward Wild, FRCP, PhD; Tiago Mestre, MD, PhD; & Jee-Young Lee, MD, PhD 
Editor: Lorraine Kalia, MD, PhD    

Huntington’s disease (HD) is at the forefront of development of gene modification therapies for movement disorders. Here are the opinions from the two HD experts, Prof. Wild and Prof. Mestre, on the current advances in HD genetics and future prospects for HD therapies. Our understanding of the clinical development and progression of HD has relied on large longitudinal cohort studies.  Prof. Lee discusses the launching of the first national cohort of HD patients in South Korea, an East Asian country where HD had been scarcely investigated to date.  

1. What are the most important recent discoveries in HD genetics?  

Prof. Wild: 

Without doubt, the biggest genetic breakthroughs in Huntington’s disease recently have been the new insights into genetic modifiers of HD. It is well-known that longer CAG repeats in the HTT gene are associated with earlier diagnosis of ‘manifest’ HD,[1] but CAG repeat length is a far-from-perfect predictor in individual cases. What’s more, earlier-than-expected or later-than-expected onset has been shown to cluster in families,[2] implying the existence of heritable genetic factors beyond CAG repeat length that may influence the natural history of HD. Previous reports of such genetic modifiers have not been replicated, largely because of a lack of sufficiently large cohorts to power the studies. That changed with a new generation of genome-wide association studies leveraging the huge and ever-growing ENROLL-HD cohort,[3] combined with banked samples and data from previous large studies. This work has been led by the Genetic Modifiers of HD Consortium (GeM-HD) and has led to two sets of related insights. 

In the first of these GWA studies,[4] a surprising number of the top ‘hits’ all pointed to genes like FAN1 and MLH3, whose protein products are components of the machinery that repairs DNA, particularly the mismatch repair pathway which detects, excises and replaces improperly-paired bases. The immediate suspicion arose that these genes could be acting to alter the rate of progression of HD pathology via the known phenomenon of somatic instability – the tendency of CAG repeats to expand in certain cells of the body, most notably the striatum which is most vulnerable in HD. Bigger CAG repeat tracts means a more toxic mutant huntingtin protein. The tempting conclusion was that minor changes in the behaviour of these DNA repair proteins could increase or decrease the rate at which extra CAGs are erroneously added to HTT exon 1 as the years go by, accelerating or decelerating motor onset. This concept was soon reaffirmed and augmented by a study leveraging deeper phenotyping in the TRACK-HD study[5] which identified MSH3, another mismatch repair gene, as a modifier of the rate of clinical progression. 

The great thing about these GWA findings is that, in the words of geneticist Jim Gusella,[6] “Mother Nature has done the experiment” and shown that onset and progression of HD can be altered in real people by these genetic differences. That means pursuing them as potential therapeutic targets is, in theory, guaranteed to work – if the beneficial effects can be mimicked or detrimental ones blocked safely. Naturally, it takes a lot of work to go from a genetic discovery to a drug, but progress in this area has been impressive, with mechanistic insights emerging thick and fast into how each candidate gene and mutation might interact with somatic instability, and multiple teams already announcing therapeutic programs[7] targeting them with clinical trial timelines as early as this year. 

Recently, an even bigger iteration of the GeM-HD GWA study[8] threw up some important results concerning the HTT gene itself. Typically, the CAG repeat tract in exon 1 is immediately succeeded by the sequence CAA-CAG. CAA encodes glutamine, just as CAG does, so in most cases the number of glutamines in the protein is actually 2 more than the number of pure CAGs in the gene. But a minority of people instead have a tract that contains two CAAs or is a pure run of CAGs. It turns out that this makes a big difference to age of onset in HD: a missing CAA interruption accelerated onset by 13 years, while the extra CAA delayed it by 6 years. Intriguingly, it’s not the number of polyglutamines directly encoded by these different sequences that makes them so influential, but rather some property of the DNA or RNA, most likely – though not yet proven – a distinct effect on DNA repair and somatic instability. 

Prof. Mestre: 

HD is a fine example of how the understanding of a neurodegenerative disorder described initially as a clinical syndrome with familial aggregation[9] changed dramatically with the discovery of the associated gene and a trinucleotide repeat expansion as a pathological mechanism (CAG repeat in Exon 1 of the Huntingtin (HTT) gene in chromosome 4[10] with significant instability (expansion), especially in the context of paternal transmission.[11] . This discovery allowed the ability to establish a definite diagnosis in life and identify individuals at risk of developing the clinical syndrome, which enabled the study of the prodromal phases of the disease in large cohorts.[12] In addition, the ability to genetically diagnose HD revealed that an HD clinical syndrome may not always be associated with the HTT gene but with other genes (HD phenocopies). 

Although age and CAG repeat number are the strongest predictors of time to phenoconversion at a group level[13], clinical practice and research teach us that there is significant variability at an individual level, both with age of phenoconversion and clinical presentation. In recent years, genetic studies have provided further insights into additional mechanisms that could explain this variability and added to the initial studies of the Venezuelan cohort in Maracaibo Lake[2] documenting both additional genetic and environmental factors to explain the variability of the age of onset. An important discovery was the identification of DNA-repair genes as modifiers of the age of onset in HD in genome-wide association studies (GWAS): FAN1 nuclease, LIG1 ligase and mismatch repair genes MLH1, MSH3, PMS1, PMS2 [14]. For example, variants in the MSH3 gene have been associated with the rate of somatic expansion, age of phenoconversion and disease progression[15].  

Another important finding by various independent research groups is the role of the variants of an interrupting CAA-CAG sequence in the HTT gene located after an uninterrupted (CAG)n segment and not included in currently available diagnostic tests. Its shortening (CAG-CAG - loss of interruption variant) or lengthening (CAA-CAGx2 - duplication of interruption variant) determines distinct uninterrupted CAG lengths and has been found to be associated with a shorter or longer time to phenoconversion, respectively. These variants are very rare in individuals with a fully penetrant allele but may be more prevalent (thus more relevant) in symptomatic subjects with reduced penetrance alleles (36–39 CAG repeats), namely, for the loss of interruption variant.  

Altogether, these novel genetic discoveries have revived the seminal findings from three decades ago of significant somatic mosaicism of the CAG repeats of the HTT gene in the brain[16] and are currently being explored for their therapeutic potential in disease modification for HD.  

2. What has been learned from the GENERATION-HD1 trial? 

Prof. Wild: 

GENERATION-HD1[17] was the first phase 3 study of a targeted huntingtin-lowering drug, the antisense oligonucleotide (ASO) tominersen. It was launched in 2018 after the first-in-human study that started in 2015 showed, to much excitement and celebration, that tominersen lowered mutant huntingtin concentration in CSF in a dose-dependent manner[18]. I was intimately involved in the design and conduct of both trials and gave the first dose of the drug to an HD patient in 2015. GENERATION-HD1 enrolled 791 patients with early manifest HD and randomised them to placebo or treatment with 120 mg of tominersen given by intrathecal bolus injection, 8-weekly or 16-weekly. The trial was expected to read out in 2022 but, in March 2021, we received the heartbreaking news that all dosing had been halted[19] on the recommendation of the independent data monitoring committee. While there was no formally-defined safety signal or futility analysis, the subsequent data presentations[20] made it obvious that patients in the 8-week arm were doing significantly worse than placebo on the main outcome measures, the composite Unified Huntington’s Disease Rating Scale (cUHDRS) and total functional capacity score, while the 16-week patients were not significantly different from placebo but certainly had not been heading in the beneficial direction. 

The devastating news was a significant setback for the development of disease-modifying therapeutics for HD, but I take comfort from the truism that the only failed trial is one that we do not learn from. The team at Roche, the sponsor, has been working ceaselessly to analyse, understand and present the ocean of data from GENERATION-HD1 that landed on them a year earlier than expected, and it is certain that this experience will inform all future HD trials. 

What went wrong? My view, for what it’s worth, is that the issue was most likely caused by a generic off-target effect of exposing vulnerable HD brains to doses of ASO that were, in retrospect, too high. The highest dose of a second-generation MOE-gapmer ASO[21] that has been given to humans is 120 mg and, crucially, all patients assigned to active treatment received two doses 28 days apart as a ‘loading’ regime. If we look back to the first-in-human trial,[18] we can see that with higher ASO doses at monthly intervals, there was a rise in CSF neurofilament light (NFL) level and ventricular volume. This was recapitulated when those 46 patients all entered the open-label extension (OLE) to that trial.[22] Curiouser still, the NFL rise turned out to be self-limiting, starting to fall by around 5 months, even in the face of gradually increasing mHTT suppression, which did not level out until nearly a year in. In the OLE, we also saw quite frequent increases in CSF leukocytes and protein levels, more so in patients on the higher-frequency dosing regime. To me this implies a degree of neuroinflammation – a known possible effect of the ASO backbone[23] – occurring early after treatment initiation, causing NFL release, but apparently with a self-limiting component. 

These previously seen phenomena foreshadowed what happened later in GENERATION-HD1. A big surprise was that despite the ventricular enlargement, the volume of brain parenchyma did not decrease in treated patients, perhaps implying altered CSF dynamics rather than accelerated atrophy with ex-vacuo dilatation. This could be caused by the leukocytes and protein impairing absorption, or a direct effect of the ASO on CSF flow. 

Many have expressed concern or indeed certainty that these results are proof that lowering huntingtin without an allele-selective approach is too dangerous because of the risk of side-effects from loss of wild-type huntingtin function. I do not think this conclusion is supported by the data, for the simple fact that NFL, having risen early well before huntingtin was maximally suppressed, started to fall spontaneously in the presence of ever-increasing huntingtin suppression. To me this is inconsistent with an effect linked to wild-type huntingtin lowering. Moreover, in this program, it is impossible to disentangle drug exposure from huntingtin-lowering, because the patients with the lowest huntingtin troughs were, in general, the patients who received the highest number of milligrams of tominersen overall. 

Recently, Roche announced that a hypothesis-driven post-hoc analysis[24] had shown that, if patients were divided into subgroups on the basis of CAG count and age, younger patients with lower CAG counts generally fared better, with the final point estimates for clinical outcomes ending up on the favourable side of placebo, though of course since this was post-hoc, no statistical significance was tested for or claimed. I interpret this as evidence that younger, healthier brains are more resilient to the undesirable effects of high-milligram ASO exposure. It follows that lowering the dose might be able to help older or sicker brains too. Rightly in my view, Roche has announced a plan to step back along the pipeline and undertake one more trial, to see if we can find a therapeutic window. This will focus on younger, lower-CAG patients and lower doses of drug and will doubtless have a close focus on safety and biomarkers as early indicators of harm or benefit. 

Prof. Mestre: 

GENERATION-HD1 trial was the first phase III intervention study of an HTT-lowering therapy developed for disease modification in HD. More specifically, GENERATION-HD1 evaluated the efficacy of the non-allele specific antisense oligonucleotide (ASO) tominersen after promising results from the pivotal first-in-human IONIS-HD study with the demonstration of a reduction in CSF mutated HTT protein in a dose-dependent manner after repeated intrathecal administration. GENERATION-HD1 was a large trial involving 791 participants diagnosed with manifest HD at early stages and randomized to tominersen 120 mg q8 weeks, or tominersen q16 weeks alternating with placebo or placebo q8 weeks. Study drug administration was halted after disappointing news came to light in March 2021 of an unfavourable benefit/risk profile. Since then, we have learned that in the group of tominersen 120 mg q8 weeks, the change from baseline of primary clinical outcome measures, a composite Unified Huntington’s Disease Rating Scale (cUHDRS) and the UHDRS total functional capacity, had a greater worsening in comparison with placebo, while there was no difference from placebo groups and those receiving tominersen q16 weeks. The study sponsor followed study participants who stayed in the trial after study treatment discontinuation and conducted pre-determined and post-hoc analyses on clinical, imaging, and wet biomarkers collected as per study protocol. Full analyses of these data are still not in the public domain and may shed more light on the study results and determine how reversible (or not) are the observed changes in efficacy outcomes. Recently, the study sponsor presented data on post-hoc subgroup analyses based on age and CAG repeat length that suggested a hypothetical better outcome (different from placebo) for primary efficacy outcomes and other readouts in the group of younger patients with a lower CAG repeat length. It is important to highlight that this difference was not statistically significant and thus may represent an incidental finding. As with any post-hoc analyses for which a study was not initially powered or designed, the risk of false-positive findings is high. Nevertheless, these data prompted the announcement of a new clinical trial of tominersen for younger, lower-CAG patients and lower tominersen doses that will certainly provide additional (perhaps final) evidence for the effectiveness or safety of this non-allele specific ASO and warrants cautious planning and monitoring in the face of the main results of GENERATION-HD1. 

Despite negative efficacy results, GENERATION-HD1 has already become a landmark study with many questions to be posed, for which we do not still have all the answers. Some important lines of inquiry have been put forward. An important question is the role of allele-specificity in the effect of HTT-lowering therapies. In other words, to what extent did the reduction of normal HTT contribute to the observed findings in GENERATION-HD1 with more intense HTT-lowering. Another hypothesis is the potential off-target effects of ASO, namely of other genes or pro-inflammatory events triggered by ASO administration that could lead to more severe and faster neurodegeneration. Heightened neuroinflammation already described in other ASO drug development programs for other conditions is another hypothesis to be considered seriously. GENERATION-HD1 also teaches us about the challenges of GO/NO GO decisions early the drug development. IONIS study documented an increase in neurofilament light chain after exposure to tominersen (followed by a reduction) and an increase in ventricular volume. To what extent these changes were premonitory of the adverse outcome found in GENERATION-HD1 requires further scrutiny. Last, whatever the final lessons learned from the GENERATION-HD1 program, these are bound to influence other HTT-lowering therapeutic pipelines. 

3. What are new therapeutic candidates for targeting mutant HTT?  

Prof. Wild: 

Thankfully, the concept of huntingtin-lowering has survived the shock of the tominersen news, and is abundantly rich, with new approaches and clinical trials already underway and starting soon. In the ASO realm, following the news that their first two candidates did not lower huntingtin measurably, Wave Life Sciences is back on the horse testing a new-generation ASO[25] that aims to selectively lower mutant huntingtin by targeting SNPs on the same HTT allele as the CAG expansion. Vico Therapeutics has an unorthodox but potentially high-reward approach targeting the RNA that arises from CAG repeats in DNA.[26] In principle, this should be at least somewhat allele-selective, because more CAGs mean more potential for ASO binding. The potential downside is that this ASO would also alter the expression of other polyCAG genes; but this may prove safe, or at least better than the unfettered progression of HD. The company has an HD program[27] but we do not yet know whether the first trial will include HD patients or focus on other CAG repeat diseases. 

Meanwhile, since June 2020, we have officially been living in the age of gene therapy for HD. Uniqure announced the first patients had been treated with AMT-130[28], their engineered adeno-associated virus that programs neurons to express a microRNA which suppresses the translation of huntingtin mRNA into protein. In principle, this is a one-shot treatment that could have lifelong effects. The main drawbacks are around delivery: the AAV has to be injected neurosurgically into brain parenchyma, which of course comes with risks and limits the volume that can be dosed. Uniqure is targeting caudate and putamen[29] with the hope this will be potent in itself and also produce axonal spread to other brain regions. As of May,[30] the company had completed 32 neurosurgical procedures and shown satisfactory one-year safety results from the first ten. It has recently expanded the trial to Europe.[31] It remains to be seen whether this approach will produce detectable CSF huntingtin lowering, because the treated area is such a tiny proportion of the total brain. It is certainly possible that intrastriatal administration could be clinically effective without significantly lowering CSF huntingtin. This program will be a slow burn, and several more gene therapies are on the way using various combinations of AAV, cargo and delivery method. 

To my mind, the most exciting approach that’s really blossoming is the use of orally bioavailable splicing modulators that raise the prospect of a huntingtin-lowering pill. Risdiplam for the treatment of spinal muscular atrophy[32] was the first CNS drug in this class to get FDA approval. In HD, these compounds rely on three rare pieces of luck[33]: first, the HTT gene happens to contain a ‘cryptic exon’, usually skipped during splicing of the pre-mRNA. Second, that exon contains a premature stop codon. And third, it is preceded by a motif that can be targeted by a suitable small molecule, resulting in inclusion rather than skipping of the exon. This upgrades the exon from cryptic to ‘poison’: the presence of the stop codon unaccompanied by the proper RNA context triggers nonsense-mediated decay of the whole transcript. At least two companies have clinical candidates targeting this mechanism: branaplam from Novartis and PTC518 from PTC Therapeutics. Branaplam was under investigation as a treatment for SMA (now discontinued for that indication) when it was unexpectedly discovered that it lowered huntingtin by this mechanism; PTC518 is designed specifically for HD and has been shown to lower huntingtin safely in healthy controls. Novartis’ trial, Vibrant-HD,[34] is already underway, while PTC expects to dose in its Pivot-HD trial [35] in the next month or two. 

So, while it’s been an even more challenging year for the HD community than it has for the rest of the world, rumours of the death of huntingtin lowering were clearly greatly exaggerated. The full story of tominersen will have at least one more chapter; we have many other allele-selective and nonselective approaches in the pipeline; we know now that NFL and ventricular volume can be early signals to inform go/no-go decisions; and novel genetic discoveries have given us several promising new therapeutic approaches that Mother Nature has already put to the test. 

Prof. Mestre: 

The field of HTT-lowering therapies maintains its vitality after the unexpected negative results of GENERATION-HD1. HD lives a golden era of therapeutic development with various programs currently active in clinical phase to test various strategies for human HTT-lowering. In the ASO field, the study SELECT-HD is underway to test an allele-specific ASO with new biochemistry after two earlier phase Ib/2a studies PRECISION-HD1 and HD2 by the same sponsor failed to show successful target engagement. This program offers the possibility to evaluate the role of allele-specificity for HTT-lowering strategies, if target engagement is documented successfully in SELECT-HD study.  

Another program that is well underway in clinical phase relies on an RNA interference strategy. In June 2020, a phase I/II clinical trial started to evaluate a gene therapy named AMT-130[31] consisting of a viral vector containing microRNA being administered through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the caudate and putamen. This is a five-year study, with an 18-month core study period followed by unblinded long-term follow-up. This approach offers a one-time treatment and direct targeting of core brain structures involved in HD. The potential drawbacks concern the safety and tolerability of an irreversible intervention, the still unknown effect of non-allele specific strategies and the fact that other areas of the brain that are part of HD neurodegeneration, such as the cortex, are not targeted. The sponsor plans to provide more complete efficacy and safety data in the first half of 2023. 

The most exciting candidates for disease modification in HD are splicing modifiers, mainly due to a convenient oral administration with non-daily dosing. An HD pill to delay disease progression would be a revolutionary yet practical proposition to the lives of people living with HD. Two programs have now entered clinical phase. Branaplam is a splicing modifier studied for Spinal Muscle Atrophy Type I that was found to have an off-target effect in the HTT gene and PTC518 is an HD-specific molecule. The Vibrant-HD (branaplam)[34] and Pivot-HD (PTC518)[35] are currently recruiting study participants.  

Finally, the therapeutic potential of somatic instability is currently being evaluated in a two-year follow-up observational study SHIELD-HD of early manifest and premanifest individuals evaluating the association of DNA damage repair gene expression with HD-related clinical outcomes and promising biomarkers such as neurofilament light chain. The modulation of somatic instability requires intracerebral-ventricular administration and targeting of both the striatum and cortex. 

The landscape of HD therapeutic development in the areas of disease modification is flourishing, and new chapters are expected for HTT-lowering therapies. The knowledge derived from these efforts will help to understand the intricacies of targeting core biological pathways underlining complex brain diseases, paving the path for a new era of target-specific therapies for neurodegenerative movement disorders. 

Why set up the first nationwide cohort of HD in South Korea? 

Prof. Lee: 

So far, HD has been known as an extremely rare disease in the East Asian region, and the clinical and epidemiological data on Korean HD patients has been scarce. A recent survey of movement disorders specialists in Korea revealed that physicians are really in need of clinical data and practice guidelines for the management of their HD patients in Korea. The up-to-date epidemiology analysis using the Rare Intractable Disease Registry recently introduced by the Korean Government revealed the annual incidence of HD of 0.29 per 100,000 and the estimated ten-year prevalence of 2.2 per 100,000 in Korea. The prevalence of HD in Korea is not as rare as previously thought, and it may be around half of the average prevalence in the Caucasian population, which is quite important for world health if the new innovative therapeutics are successfully developed. Because of improved education and the introduction of gene tests in Korea, the annual number of newly diagnosed cases has increased and physicians’ knowledge of this disorder seems to have substantially improved in recent years. However, more than half of HD patients in Korea are still not regularly followed up in medical institutions after diagnosis, probably due to negative expectations by patients themselves or to insufficient management by physicians, no treatment guidelines, and few resources for therapeutics in Korea.  

To overcome the current situation, the Korean Huntington’s disease study group was recently organized with the support of the Korean Movement Disorders Society, and the first national Korean HD cohort registry was launched. The cohort is aimed to enroll 300 patients until the end of 2023, and the clinical and genetic data collected from the cohort could improve the understanding of Korean HD patients and help create national practice guidelines. The Korean investigators are eager to support the progress of new disease-modifying therapeutics development and will be ready to contribute to the global effort.  



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