Developing Therapeutics for Huntington’s Disease: Challenges, Opportunities and the Future

The gene responsible for Huntington’s Disease (HD), HTT, was discovered almost 30 years ago, yet there is no still cure, and only limited therapeutics are available for this debilitating neurodegenerative condition.

In this two-part interview series, Technology Networks finds out more about some of the reasons for the current lack of treatment options for HD patients and explores how this could change in the future.

For our second interview, Dr. Christian Landles, senior research associate in neurodegenerative diseases at UCL Queen Square Institute of Neurology, explains why it is so challenging to develop therapeutics for rare diseases such as HD, and discusses the potential of approaches that target mutant huntingtin protein to improve treatment options for HD patients.

Anna MacDonald (AM): What therapeutic options are currently available for HD?

Christian Landles (CL): Since HD is an autosomal-dominant inherited neurodegenerative disorder, the disease is endemic to all populations, and currently there are no treatments which can avert or delay the progression of this devasting disease. Therefore, in the absence of an effective disease-modifying therapy, the current clinical care of patients focuses on expert assessments and in the management of treating the symptoms associated with this disease that maximizes the patients’ function and quality of life.

At present, preclinical studies or clinal trials for the treatment of HD are being planned or are underway which utilize novel agents which either aims to silence/lower the HTT gene (thereby diminishing the production of the mutant protein) or which seeks to stop/slow-down the somatic expansion of the HTT gene (thereby reducing the CAG pathogenic repeat threshold). Therapeutic approaches advancing fastest and gaining the most momentum would be in the development of agents that aim to lower the HTT gene by gene silencing and gene editing, but interest still very much exists for the identification of potential small molecule drug targets and canonical screening processes such as the one used to discover the experimental orphan drug “Branaplam” (LMI070, a pyridazine derivative) as an RNA splicing modulator for the treatment of spinal muscular atrophy (SMA). Intriguingly, in the process of clinically testing Branaplam in SMA, it was also observed that this investigational therapy also lowered the levels of the HTT mRNA by a similar mechanism. With much delight therefore it has been granted fast track status by the FDA to launch a phase II clinical Branaplam trial to premanifest HD patients.

AM: Why are these options so limited? Can you tell us more about the difficulties of developing a therapy for a rare disease such as HD?

CL: The options available for treating HD disease are so limited due to the complex multi-functional role that huntingtin plays within the cell, which ideally must be preserved upon the administration of any therapeutic intervention. Since the mapping (1980s) and cloning (1990s) of the HTT gene, an explosion of research relying on various approaches has provided many molecular insights into the normal function of huntingtin and the molecular basis of the disease. Critically, huntingtin is an essential gene involved in the development and function of the central nervous system; therefore, any therapeutic HTT lowering strategy must aim to protect and maintain these vital processes, since when targeting any mechanisms driven by mutant huntingtin, this should not counterproductively also induce a loss-of-function of wild type huntingtin.

Consequently, most efforts towards understanding the pathogenesis of HD have been primarily driven by the toxic gain-of-function hypothesis and attempts to determine the mechanisms by which the expansion of the polyQ tract is linked to critical alterations in huntingtin structure and function, and how this cumulatively causes neurodegeneration at a cellular and systems level. For this reason, up until recently, it has been extremely difficult therefore to develop an effective therapy for a rare disease such as HD, since countless preclinical studies have failed as they could not deliver a multifactorial therapy which could target all the cellular pathways which are affected in the neuropathology of HD. Undoubtably, that is not to imply that these research studies are not worthy. Rather, in stark contrast, this research has now driven the HD field into accepting that the safest way to combat this debilitating disease – although still very challenging in itself – would be to target this disease from the top and go for the HTT gene itself.

AM: Interest is growing in the development of therapies that could lower mutant huntingtin protein. Can you explain the role this protein plays in HD, the benefits of targeting it and progress so far?

CL: Undoubtably, much interest exists in the development of therapies that specifically lower the mutant huntingtin protein since HD is primarily considered to be a toxic gain-of-function disorder. Research into the functional complexity of this protein is now converging on understanding how the mutation of the polyQ tract expansion is linked to alterations in protein structure; identifying what critical toxic conformational changes are pathogenic to induce cytotoxicity; and generally elucidating pathogenic mechanisms such as the proteolytic fragmentation processes and aberrant splicing mechanisms which generates the highly toxic N-terminal fragments of huntingtin, and understanding the consequences of its post-translational modification, to name a few.

Specifically, what isoforms of the huntingtin protein are consequently responsible for cytotoxicity in HD remains to be defined, and answering this question is by no means straightforward. With that said, it is pertinent for the HD research field that research technologies such as HTRF, AlphaLISA, Simoa, and SMC assays offer critical research tools to detect for example, the different isoforms of the huntingtin protein to help drive research in this disease space forward and into therapeutics. Undoubtably, understanding the pathogenic mechanisms in HD, and the assessment of preclinical studies and clinical trials would be confounded without such technology innovations that key industrial players have provided to the HD research community.

The benefits of targeting the HTT gene with nucleotide-based therapies such as with antisense oligonucleotides (ASOs) and RNA-interference (RNAi) at the RNA level, or with zinc finger proteins (ZFPs) and CRISPR-Cas9 systems at the DNA level in numerous preclinic research studies is ever-more becoming self-evident with the increasing number of publications proving proof-of-concept target engagement as observed in “read-outs”, indicative of successfully lowering or ameliorating levels of the toxic mutant huntingtin protein. However, although much progress has been made, it is still unclear which therapeutic approaches are most rationale as each have their own limitations, and alongside this, it is still crucial to understand what the best huntingtin protein target is for these “read-out” assays. Many such biological therapies have been administrated and developed to various stages of clinical phase trials with differing levels of success or failures/insufficient data, but fundamentally, the HD field must now reinvigorate its efforts to understand and identify the most promising avenues, especially for halted programs; ultimately, until we analyze and understand all the data, we will not completely know whether these agents did anything to alleviate or worsened HD symptoms, or hypothetically, if these agents were just not potent enough to ameliorate the symptoms of HD. Furthermore, it must be noted the scale-up in safety, tolerability and distribution, etc., required from therapeutically targeting preclinical models such as small mice, mini-pigs, etc., to the whole brain of clinical HD patients is an enormous investment of not only funds but of time, which is already a scarce and precious resource for those diagnosed with HD.

AM: How are approaches to rare disease drug discovery changing? What further changes could we see in the future?

CL: As it pertains to the approaches to rare disease drug discovery, a focal point is understanding more about the safe usage and limitations of use for novel therapeutic agents. When considering nucleotide-based therapies in HD, future challenges include monitoring/assessing/negating any harmful off-target effects throughout development and administration, especially if using DNA-targeting therapies which carry a greater risk due to their permanent mechanism/mode of action. The specificity of these agents must be precise to target only the mutant HTT allele (if that is the intention) without inadvertently lowering the wild type HTT allele or any other transcripts and/or genes that contains similar CAG sequences. In the same vein, the safety of wild type huntingtin suppression is not fully understood and has yet to be studied into longevity, especially for therapeutic agents that may also be unintentionally lower both HTT alleles. Therefore, as an HD community, we must better understand the risks associated with administrating non-allele selective therapies or banking on allele selective approaches when they are much further away from the clinic; since targeting only the mutant huntingtin allele is by no means straightforward due to its almost identical similarity to its wild-type counterpart. In addition, solving the uncertainty/risks involved with maintaining longevity of treatment is not straightforward – one fundamental difference between the RNA- and DNA-targeting therapies is in their longevity, with DNA-approaches (i.e., ZFP and CRISPR/Cas9) offering permanent suppression, whilst RNA-approaches (ASOs and RNAi) being more temporary. Consequently, whereas the disadvantage of the temporary nature of the RNA-targeting technologies is the need for repeated administration, for which the sustainability of which is unknown, etc., the long-term consequences of DNA-targeting technologies involving permanent gene-editing, carries a greater risk due to their permanent nature after just a single administration.

Though still with reservation, I would predict that our understanding into the molecular mechanisms and our advancements in therapeutics for the treatment of rare diseases such as HD will surely move us closer to finding the cure. Over the next decade we are likely to see advances which reduces the limitations discussed previously, but also see technical advances which aids for the delivery of these therapeutic agents to where they are needed to have clinical significance. For example, we must refine therapeutic drugs which can freely cross the blood-brain-barrier to avoid the risk of invasive surgical administrative procedures; refine therapies that when administrated can target/transduce more cell types to facilitate a much greater CNS distribution, etc.

For many years, the HD field quite frankly did not possess the technologies needed to assess and accurately quantify disease progression and therapeutic efficacy in those affected by HD, especially at very early stages prior to clinical manifestation of recognizable symptoms. Unlike diseases of the human body that are more accessible and can be accessed via a biopsy or a quick scan, maladies of the brain tend to be either too invasive or too lengthy/open to interpretation in most cases and does not easily scale-up for large longitudinal studies. Fortunately, despite some initial concerns about the accuracy in measuring HD biomarkers in patient biofluids to track changes observed in the brain, we are now entering a new era where the proteins such as NfL, MAPT, and CHI3L1, along with mutant huntingtin are being used as biomarkers to assess disease status and/or assess the impact of the administration of any therapeutic intervention, which is critical for more recent clinical trials that include premanifest HD patients.

That said, despite now possessing this technology, there are still notable limitations with these bioassays. Namely, they are limited in scope since only a few targets or mutant isoforms of huntingtin have currently been identified, inherently complicated since their performance relies on the avidity/availability/ability to detect the target protein of interest of these antibody-based detection bioassays, requires greater sensitivity to detect them in complex patient biofluids at low “femtomolar” concentrations, and cost prohibitive to most basic research laboratories as it requires very specialist machine technologies and operators to set up and establish “in-house”.

Dr. Christian Landles was speaking to Anna MacDonald, Science Writer for Technology Networks.