The gene responsible for Huntingtons Disease (HD), HTT, was discovered almost 30 years ago, but there isn''t a cure yet, and only limited therapeutics are available for this debilitating neurodegenerative condition.
Dr. Christian Landles, a senior research associate in neurodegenerative diseases at the UCL Queen Square Institute of Neurology, discusses why therapeutic therapy for rare ailments such as HD is so difficult, and discusses the possibility of approaches that target mutant huntingtin protein to improve treatment options for HD patients.
What therapeutic options are currently available for HD, according to Anna MacDonald (AM).
Christian Landles (CL): Since HD is an autosomal-dominant inherited neurodegenerative disorder, the disease is endemic to all individuals, and there are no medications which can prevent or delay the progression of this devasting disease. However, the current clinical care of patients focuses on expert evaluations and in the management of the symptoms associated with this disease.
Currently, preclinical studies or clinal trials for HD are being launched, which utilize novel agents that aims to silence/lowen the HTT gene by gene silencing and gene editing, but also which are attempting to stop/slow-down the somatic growth of the HTT gene. Consequently, the FDA has granted approval to begin a phase II clinical Branaplam trial to premanifest HD patients.
AM: Why are these options so limited? Can you please tell us more about the difficulties of developing a therapy for a rare disease such as HD?
CL: The difficulty in treating HD disease is limited due to the complex multi-functional function that huntingtin plays within the cell, which should be preserved upon the use of any therapeutic therapy. Despite the mapping (1980s) and cloning (1990s) of the HTT gene, an explosion of research using diverse methods has provided many molecular insights into huntingtin''s normal function and the molecular basis of the disease. Therefore, any therapeutic HTT lowering strategy must aim to protect and maintain these crucial processes when
Consequently, most attempts towards understanding HD''s pathogenesis 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 cellular and systems levels. Rather, this research has now enabled the HD field to accept that the safest approach to combat this debilitating disease would be to target this disease from the top and go for the H
AM: The focus is on the development of therapies that might reduce the mutant huntingtin protein. Can you explain the role this protein plays in HD, how long it has been zieled, and how it has improved so far?
CL: There''s undoubtedly a lot of interest in the development of therapies that significantly lower the mutant huntingtin protein because HD is primarily considered to be a toxic gain-of-function disorder. Scientists are now assessing how the mutation of the polyQ tract expansion is linked to protein structure changes; examining what critical toxic conformational modifications are pathogenic to induce cytotoxicity; and examining pathogenic mechanisms such as the highly toxic N-terminal fragments of huntingtin, and understanding its post-translation
Generally, what isoforms of the huntingtin protein are therefore responsible for cytotoxicity in HD remains to be identified, and this question is no longer straightforward. For the HD research field, it is important that research technologies such as HTRF, AlphaLISA, Simoa, and SMC assays provide 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. Without such technology advancements, there might be
In many preclinic research studies, the value of targeting the HTT gene with nucleotide-based therapies such as antisense oligonucleotides (ASOs) and RNA-interference (RNAi) at the DNA level is increasing, although many publications have shown that each agent has their own limitations, and it is still critical to consider whether these therapies are effective at alleviating or alleviating HD symptoms. Finally, the scale-up in safety, tolerability, and distribution, required from therapeutic
AM: How are approaches to rare disease drug discovery evolving? What future changes might be made?
Considering the possibility of nucleotide-based therapies in HD, future challenges include monitoring/evaluating/negating any harmful off-target effects throughout development and administration, mainly if targeting only the mutant HTT allele (if that is the intention)
Although still with reservations, I''d anticipate that our understanding of molecular mechanisms and our advancements in therapeutics for treatment of rare diseases such as HD will surely guide us closer to finding the cure. Over the next decade, we are likely to see advancements that reduce the limitations discussed previously, but also see technical advances which help the delivery of these therapeutic drugs to clinical significance. For example, we must refine therapeutic drugs that when administered, can target/transduce more cell types, which also facilitate a much greater CNS distribution.
Despite some initial concerns about the accuracy in measuring HD biomarkers in patient biofluids to track disease progression and therapeutic effectiveness, we are now entering a new era in which proteins such as NfL, MAPT, and mutant huntingtin are being used as biomarkers to determine disease status and/or evaluate the effects of any therapeutic intervention.
Despite this fact, these bioassays are still substantial limitations. Specifically, they are limited in scope because only a few targets or mutant isoforms of huntingtin have been identified, and their performance is dependent on the avidity/availability/ability to detect the target protein of interest of these antibody-based detection bioassays, and they are cost prohibitive to most basic research laboratories. It requires very expert machine technologies and operators to establish and establish in-house.