Driving Forward Huntington’s Disease Research

Huntington’s disease (HD) is a neurodegenerative condition caused by a mutation in the HTT gene. Since there is still no cure for the disease, treatments are limited to managing symptoms to maximize patients’ quality of life. Ongoing research to increase our knowledge of the mechanisms underpinning HD and identify biomarkers associated with the condition is helping to progress the development of improved treatment options.

In this two-part interview series, Technology Networks learns about some of the latest breakthroughs in HD research and explores novel therapeutic approaches currently in development.

For our first interview, Dr. Christian Landles, senior research associate in neurodegenerative diseases at UCL Queen Square Institute of Neurology, highlights some of the progress made in recent years to improve our understanding of HD and its drivers. In this interview, Christian also discusses the importance of HD biomarker characterization and identification and the critical role that technology plays in driving HD research forward.

Anna MacDonald (AM): Can you share some highlights of the latest breakthroughs in HD research?

Christian Landles (CL): As a scientific researcher working at the bench in the laboratory, these are undoubtably exciting times for investigating HD. With the amalgamation of many research disciplines (including teams of neurobiologists, clinicians, pharmacologists and medicinal chemists), collectively, we are in the best position to enable significant progress in our understandings into the treatments of HD. Furthermore, with great advancements in technology, automation and artificial intelligence, etc., over the past decade, this progressive innovation has allowed us to study HD and other devastating disorders at a much more rapid pace than what we could have ever imagined. Moreover, it is great to now be able to witness the rewards of these innovations coming to fruition in our preclinical and clinical studies. Over the past decade I can certainly say that I have observed progressively more and more optimistic data coming out from our HD research community, where our combined approaches do seem to be culminating in the right direction for the eventual successful therapeutic treatment of HD in patients.

In terms of recent years, I would like to highlight two breakthroughs: our understanding of somatic instability as an additional driver of HD disease onset and progression, and the impressive work done towards identifying important HD biomarkers which are now being used to monitor and track disease progression and/or assess the impact of therapeutic interventions at various stages and at many levels.

For many years, although CAG repeat length was recognized as “the” major determinant of age-of-onset and disease progression, a greater understanding of how genetic and environmental modifiers also contributes to the pathogenesis of HD has now become of great importance. The CAG repeat tract present in the brains of HD patients is unstable, and consequently, somatic expansion of this tract has been demonstrated to be directly correlated with an earlier age of disease onset, and indeed faster disease progression. The concept of somatic instability has already been established and recapitulated very well in many preclinical mouse models of HD for several years, and likewise, was already known to be abrogated in the absence of some key DNA mismatch repair genes. The recent scientific breakthrough came with the identification of DNA repair genes (namely, FAN1, MSH3, MLH1, PMS1, PMS2, LIG1) as modifiers of the age-of-onset and/or progression of HD through several genome-wide and/or transcriptome-wide association studies; these studies have not only underlined another causative role for somatic CAG instability in the pathogenesis of HD, but could be indicative that the threshold for pathogenic repeats in brain cells could actually be much greater than that measured in patient blood and, if correct, such a threshold in the brain remains unknown. Startlingly, any process that increases CAG repeat length could have calamitous consequences for disease prognosis through several mechanisms, including: (i) at a protein level the obvious translation of this CAG tract into a longer, more cytotoxic, polyglutamine (polyQ) protein; (ii) at an RNA level through either changing the extent to which an incomplete splicing event produces a small transcript encoding the highly pathogenic exon 1 HTT protein, by inducing aberrant repeat associated non-AUG translation (RAN) translation, or by affecting RNA secondary structures; and finally (iii) at a DNA level by affecting transcriptional regulation and/or DNA repair activities.

Until recently, very few biochemical markers had been identified and properly validated that would enable a quick and direct assessment of neuronal injury, track disease progression linked to pathology/clinical phenotype, and which could be evaluated in longitudinal studies. Moreover, of these, many are still poor candidates for therapeutic HD trials involving the delivery of disease-modifying agents to the central nervous system (CNS) since they are also markers of peripheral pathology. But critically, through recent advancements in ultrasensitive immunoassays, this has now enabled for the quantification of neurofilament light protein (NfL) from patient blood plasma and/or serum, and cerebrospinal fluid (CSF). For the first time ever, the use of NfL as a biomarker in highly sensitive bioassays can now be applied to provide pharmacodynamic readouts in preclinical studies and clinical trials to evaluate mutant HTT lowering efficacies, particularly important for premanifest HD patients where early treatment is most likely to bring the most meaningful benefit in the long-term.

AM: Why is it so important to improve the characterization and detection of HD biomarkers?

CL: In addition to improving the detection of HD biomarkers such as NfL, it is also vital to improve the characterization and detection of huntingtin protein biomarkers as well to (i) better understand the molecular pathogenesis, (ii) ensure that the levels of all soluble and aggregated isoforms of the huntingtin protein can be measured, (iii) track how these huntingtin isoforms change in relation to disease onset and progression; and (iv) assess the impact of potential therapeutic interventions in preclinical studies and clinical trials.

In particular, over the past decade, considerable progress has been made utilizing antibody-based pairing bioassays to detect the soluble mutant, wild type, and aggregated huntingtin protein on technologies such as homogeneous time-resolved fluorescence assays (HTRF), amplified luminescent proximity homogeneous assay (AlphaLISA), and Meso Scale Discovery (MSD) platforms. Furthermore, sensitive single molecule counting (SMC) bioassays have recently been established which measure soluble mutant huntingtin in patient CSF, to provide a pharmacodynamic read out in clinical trials to evaluate the HTT lowering impact and efficiency of an antisense oligonucleotide targeting the HTT transcript. These technologies provide an essential toolkit to track total soluble mutant huntingtin, soluble exon 1 huntingtin, soluble mutant huntingtin protein (excluding the exon 1 huntingtin) and total soluble full-length huntingtin (mutant and wild type) protein isoforms, as well as the aggregation of mutant huntingtin to help track disease progression. Importantly, alongside other HD biomarkers, these novel bioassays are intended to be used to compare the relative levels of huntingtin protein isoforms in a wide variety of preclinical studies of HD and to determine how these change in response to genetic or therapeutic manipulations.

AM: What has yet to be discovered or understood about the biology of the disease that technology may provide answers to?

CL: Only time will tell what remains to be discovered and understood regarding the biology of HD, but with greater advancement I am confident that better technology will have an important part to provide us with these answers. As an experienced researcher myself, when interpreting our own preclinical data from mouse models of HD, currently we must still undertake a multitude of complementary approaches to draw any final conclusions to understand the relationship between mutant huntingtin and the onset and progression of disease phenotypes. This is no easy undertaking as it means that as a lab, we must meticulously account for the planning, bench execution, data collection of our longitudinal studies, whilst then interpretating the data collected across an ever-increasing number of analytical techniques that requires a subcellular analysis at many molecular levels to give proper due diligence in understanding complicated disease phenotypes.

I’d also like to note that with the genetic certainty that comes with rare neurological diseases such as HD, the work and time that the neuroscience research community has put into tackling this devastating disease can be applied as a model for studying shared mechanisms and therapeutic development across other, more complex, neurodegenerative diseases. Similarly, it should also not be forgotten that HD is not the only trinucleotide repeat disorder; therefore, through promoting and exploring huntingtin-lowering therapeutic strategies, what we have collectively learned about targeting HD should benefit and complementarily advance our approaches and understandings into other neurological disorders as well.

I would ultimately hope that not only will advances in technology lead to meaningful insights that further our understandings of HD and other devastating disorders, but also get us answers much faster so that these diseases may one day, be perceived as being completely curable.

AM: How is the CHDI foundation helping to drive HD research with partnering labs?

CL: The CHDI foundation is a privately funded, not-for-profit biomedical research organization whose main mission is devoted to developing drugs which will either prevent, slow down, or cure HD by providing a meaningful clinical benefit to patients as fast as possible. To help drive HD research forward, and move closer to achieving their mission, CHDI works somewhat differently than more conventional funding bodies since they proactively partner with a diverse range of research laboratories all around the world. This collaborative research model has encouraged and forged connections between academic basic research, with drug discovery, and clinical development. This not-for-profit “collaborative enabler” approach has not only helped drive HD research forward at an amazing rate and made vital HD resources freely available, but it has successfully bridged the often costly time delay associated with the translational gap that frequently exists between academic and industry research partners. Remarkably, CHDI’s research influence now extends from exploratory biology to the identification/validation and development of potential therapeutic targets, and from drug discovery into the development of clinical studies/trials. Without CHDI working with the entire HD research community, I am sure that potentially promising therapeutic drugs could not progress as quickly as they have been to clinical trials in HD patients.

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