The gene responsible for Huntingtons Disease (HD), HTT, was discovered almost 30 years ago, yet there is no cure, and only limited therapies are available for this debilitating neurological condition.
For our second interview, Dr. Christian Landles, a senior research associate, Neurodegenerative Diseases at the University of Alabama, discusses why therapeutic therapy for rare diseases such as HD is so challenging, and discusses the possibilities of approaches that target mutant huntingtin protein to improve treatment options for HD patients.
What therapeutic solutions are currently available for HD, Anna MacDonald (AM)?
Christian Landles (CL): While HD is an autosomal-dominant inherited neurodegenerative disorder, the condition is endemic to all populations, and there are no therapies which may avert or delay progression of this devasting disease. Consequently, the current clinical treatment of patients focuses on expert assessment and in the management of the symptoms associated with this disease.
Preclinical trials for HD are being organized or are underway, which utilize novel agents that either aims to silence or decrease the HTT gene (thereby diminishing the production of the mutant protein) or which strive to stop/slow-down the somatic expansion of the HTT gene, according to the FDA. Upon completion of a phase II clinical Branaplam treatment, patients will be greeted with great satisfaction.
AM: Why are these options so limited? Can you? If you can tell us more about the difficulties of developing a therapy for a rare disease, such as HD?
CL: Due to the complex multi-functional function that huntingtin plays within the cell, which ideally must be preserved upon the administration of any therapeutic intervention. Consequently, any therapeutic HTT lowering strategy must aim to protect and maintain these vital processes when targeting mutant huntingtin; this should not adversely impact a loss-of-function of wild type huntingtin.
Most attempts to understand HD''s pathogenesis have been mainly driven by the toxic gain-of-function hypothesis and attempts to determine how the polyQ tract expands is linked to crucial alterations in huntingtin structure and function, as well as how this can be seen in the brain. However, these attempts have also prompted the HD field to accept that this method, although it is still quite challenging in itself, would be to target this disease from the top and go for the HTT gene itself.
AM: Interest is increasing in the development of therapies that might slash mutant huntingtin protein. Can you explain the importance this protein plays in HD, the implications of targeting it, and how it has evolved so far?
CL: While it is unlikely that much interest is invested in the development of therapies that specifically reduce the mutant huntingtin protein, HD is primarily considered to be a toxic gain-of-function disorder. While studying the functional complexity of this protein, it is now working on discovering what critical toxic conformational modifications are pathogenic to induce cytotoxicity; and developing pathogenic approaches, such as proteolytic fragmentation and aberrant splicing mechanisms, to name a few.
It is important that research technologies like HTRF, AlphaLISA, Simoa, and SMC assays can help with the development of pathogenic pathways in HD, thus ensuring that research in this disease space progresses further and later into therapeutics. Without these technology advances, key industrial actors have provided to the HD research community.
In many preclinic research studies, the benefits of targeting the HTT gene with nucleotide therapies such as antisense oligonucleotides (ASOs) and RNA-interference (RNAi) at the DNA level are becoming more apparent, although many publications have demonstrated that their expertise is most appropriate, thus, the HD field must now evaluate and identify the most promising approaches available, particularly when it comes to clinical trials. Furthermore, until we analyze and understand all data, it must be noted that,
AM: What are the approaches to rare disease drug discovery evolving? What additional changes might be made in the future?
While managing non-allele selective therapies in HD, future challenges include monitoring/assessing/negating any harmful off-target effects throughout development and administration, especially if targeting mutant HTT alleles with their permanent mechanism/mode of action. Consequently, as an HD community, the dangers of managing non-allele selective therapies, including monitoring/evaluating/negating any other harmful off-target effects, especially if targeting mutant HTT alleles with permanent suppression. Nevertheless, the long-term implications of DNA-target
Although still with caution, I would anticipate that our understanding of molecular methods and our advancements in therapeutics for treatment of rare diseases such as HD will certainly help us closer to finding the cure. Over the next decade, we will likely see advances that may alleviate the limitations discussed previously, but also technical advances that assist in the delivery of these therapeutic agents to the areas where they are required to be clinically significant. For example, we must refine therapeutic drugs that when administered can target/transduce more cell types to facilitate a significantly greater CNS
For many years, the HD field quite frankly did not have the skills necessary to accurately quantify disease progression and therapeutic effectiveness in patients affected by HD, especially in early stages prior to clinical manifestation of apparent symptoms. Fortunately, the proteins such as NfL, MAPT, and mutant huntingtin are becoming used as biomarkers to determine disease status and/or evaluate the impact of any therapeutic intervention.
Despite this being done, these bioassays are still limited in scope since only a few targets or mutant isoforms of huntingtin have been identified, and they are therefore extremely complicated because their ability to detect target proteins at low femtomolar concentrations, which requires greater sensitivity to detect them in complex patient biofluids, which are prohibitive for most basic research laboratories.