INfLUENCE-HD: Influencing juvenile-onset Huntington's disease monitoring with remote Neurofilament light quantification

Huntington's disease (HD) is a rare inherited disease that causes brain degeneration and is one of the most common inherited dementias. Every case of HD is caused by a mutation in the huntingtin gene that causes cells to produce a harmful protein that is toxic to brain cells. Typically, HD manifests in adulthood between 30-50 years. However, more severe mutations cause symptoms to present earlier. Juvenile-onset Huntington's disease (JoHD) is when HD symptoms start before the age of 21. JoHD is ultrarare making it difficult to study fully, when means it is not well understood and our ability to run clinical trials for JoHD is limited.

I have previously reported the first blood test that reflects adult-onset HD progression including the worsening of clinical symptoms and brain shrinkage measured by brain scans. This test measures a brain protein called Neurofilament light (NfL) of which levels in the cerebrospinal fluid (CSF - the fluid that surrounds the brain and spinal cord) and blood (now detectable due to ultrasensitive measurement techniques) tells us about the health of brain cells. In a small number of JoHD patients, I showed blood NfL was much higher than in healthy children.

I am now working to gain the much-needed information required to implement clinical trials in JoHD patients. Ultimately, we need robust and sensitive tools called biomarkers that can tell us whether a drug is working. However, the severity of JoHD makes it hard for these young patients to make it to clinic and to take part in research. If we could study JoHD from afar then we could collect enough data to better understand the disease.

I have developed a way to collect blood via a finger prick to measure NfL from patients who can take part in this research from their own homes. I hope this will increase the uptake of JoHD patients we can study and allow me to generate the largest cohort of these neglected patients. I am the global Chief Investigator of JOIN-HD, the first global registry study of JoHD. I will use the registry to recruit up to 100 JoHD patients to provide blood for repeated NfL measurements every 6 months over 2-years.

INfLUENCE-HD includes a major collaborative effort to use samples from existing human studies including children and young adults, right up to older adults with the HD gene. I will study NfL in these samples to generate a model for how NfL changes throughout the life of a HD mutation carrier. I will include data from brain scans to strengthen these models and provide more detailed information of the disease biology underlying NfL changes. By using existing human supplied by several collaborators, this work can proceed quickly and efficiently.

Together, this work will significantly and efficiently advance the role of NfL to help understand JoHD, predict its clinical course and accelerate the development of drugs. Further, home testing of NfL has potential of impacting other neurodegenerative conditions and transforming how patients' disease is monitored within Neurology. As a collaborator with the major pharmaceutical industry players in HD drug development, and an advisor to the Critical Path Institute, which in turn advises governmental drug regulatory agencies, I am ideally placed push this work forward to facilitate developing new treatments for this devastating illness and others.

Huntington's disease (HD) is a neurodegenerative disease caused by CAG expansions in the huntingtin gene. Typically, HD manifests in adulthood between 30-50 years. However, longer CAG repeat expansions can lead to an ultrarare (~5% of HD cases) manifestation of HD before the age of 21 years, known as Juvenile-onset Huntington's disease (JoHD). JoHD has not been studied extensively. There are currently no disease modifying therapies (DMTs) for HD, and JoHD is underrepresented in clinical trials due to inclusion criteria being >18 therefore excluding paediatric cases.

Remote assessment of JoHD patients could facilitate JoHD research by alleviating physical burden and geographical limitations on the patients and caregiver, allowing higher sample numbers to elucidate its complex natural history. Response biomarkers of neuronal damage are needed for clinical trials. I reported neurofilament light protein (NfL) as the most promising such biofluid biomarker: its level predicts onset and progression in adult-onset HD and is elevated in JoHD patients compared to healthy control children.

INfLUENCE-HD will harness remote sample and data collection in conjunction with international collaborations to apply plasma NfL to JoHD. I have developed a finger-prick blood collection method for NfL quantification that, from pilot data, is consistent with the standard venous blood measurement. I will continue to build the largest, international JoHD registry, JOIN-HD, and utilise it to recruit up to 100 JoHD patients for remote longitudinal plasma NfL quantification. My collaborators with share plasma samples for NfL quantification as well as clinical, phenotypic and neuroimaging data from their JoHD studies to amplify our efforts. I will develop a fine-grained model of NfL dynamics throughout the lifespan of HD mutation carrier in the context of macro- and micro-structural brain changes.

INfLUENCE-HD will provide the tools and understanding for clinical trials in JoHD.