Huntingtons Disease Research Is Moving Forward

Huntingtons Disease Research Is Moving Forward ...

Huntingtons disease (HD) is a neurodegenerative disease that involves a mutation in the HTT gene. Treatments are limited to managing symptoms to enhance patients'' quality of life. Ongoing research to enhance our knowledge of the mechanisms behind HD and identify biomarkers is helping to guide the development of improved treatment options.

For our first interview, Dr. Christian Landles, a senior research associate in neurodegenerative diseases at the UCL Queen Square Institute of Neurology, discusses some of the improvements we have 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, as well as the key role that technology plays in driving HD research forward.

Anna MacDonald (AM): Is it possible to share some of the recent advances in HD research?

Christian Landles (CL): These are evidently exciting times for studying HD. With the amalgamation of many research disciplines (including teams of neurobiologis, clinicians, pharmacologists, and medicinal chemists), we have now reached an agreement on how to measure HD and other harmful diseases in our preclinical and clinical trials. I have certainly demonstrated that this progressive innovation has allowed us to rapidly analyze HD and other devastating disorders in a much more concise manner than we imagined.

Two key breakthroughs have been made in the last years: our understanding of somatic instability as an additional source of HD disease onset and progression, and the enormous work undertaken to identify key HD biomarkers, which are now being utilized to monitor and monitor disease progression and/or assess the impact of therapeutic interventions at various stages and levels.

Interestingly, a higher scientific understanding of how genetic and environmental factors contributed to HD''s pathogenesis has now become of paramount significance. Through several genome-wide and transcriptome-wide association studies, this CAG repeat tract has already been established and recapitulated very well; therefore, this tract could have significant implications for disease prognosis, owing to: (i) at an RNA level by inducing aberrant repeat associated non-AUG translation; and (iii) at an DNA level by inducing

Very few biochemical markers had been identified and properly validated that would allow for a quick and direct evaluation of neuronal injury, track disease progression linked to pathology and clinical phenotype, and which might be evaluated in longitudinal studies. However, thanks to recent improvements in ultrasensitive immunoassays, the use of NfL as a biomarker has now permisted for therapeutic HD trials involving the delivery of disease-modifying agents to the central nervous system (CNS), mainly suited for premanifest

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

CL: While improving the detection of HD biomarkers such as NfL, it is also crucial to (i) better understand the molecular pathogenesis, (ii) ensure that all soluble and aggregated isoforms of the huntingtin protein can be measured, (iii) monitor how these huntingtin isoforms modify in response to disease onset and progression; and (iv) assess the implications of therapeutic therapies in preclinical studies and clinical trials.

Recently, significant improvement has been made owing to an antibody-based pairing techniques to detect the soluble mutant, wild type, and aggregated huntingtin protein, according to homogeneous time-resolved fluorescence tests (APHD) and Meso Scale Discovery (MSD). Additionally, these novel bioassays are intended to be used in conjunction with other HD research methods to help monitor disease progression.

AM: What has not been discovered or understood about the biology of the disease that technology may be to answer?

CL: Only time will tell what will be discovered and understood regarding HD''s biology, but with greater advancement I am confident that improved technology will have an important role to play in understanding these answers. As an experienced researcher myself, when interpreting our own preclinical data from HD, we must constantly monitor the history of our longitudinal studies, while then analysing the data collected across a wide spectrum of molecular levels to ensure proper due diligence in understanding developing complicated disease phenotypes.

Id also like to emphasize that, due to the increased amount of certainty that comes with rare neurological disorders such as HD, the work and effort that the neuroscience research community has put into tackling this devastating disease can be implemented as a model for sharing 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

I''d hoped that advances in technology will lead to valuable insights that will improve our understanding of HD and other devastating disorders more effectively, but also enable us to respond quickly so that these illnesses may one day be perceived as completely curable.

AM: How does the CHDI foundation assisting with HD research by partnering laboratories?

CL: The CHDI foundation is a privately funded, not-for-profit biomedical research organization, that is primarily devoted to developing therapies that will either prevent, slow down, or cure HD as quickly as possible. This collaboration enabler approach has also helped accelerate HD research progress, from exploratory biology to the identification/validation of potentially promising therapeutic therapies, and from clinical trials in HD patients.

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