UCLH-BRC/UCL researchers at the Huntington disease (HD) Centre have transformed understanding of how this fatal condition progresses and accelerated major industry-led trials of new treatments designed by her research team. The first inhuman trials of new treatments, targeting the genetic factor which causes HD, have been carried out and more are planned.
HD is an inherited disease caused by a mutation in the huntingtin gene. The mutated gene codes for a defective protein, that leads to brain changes, responsible for loss of mental and physical functions, and death. There is currently no cure and no way to slow or stop these brain changes. The discovery of biomarkers of disease progression are crucial to develop therapies, that are urgently needed.
Professor Tabrizi's team led a prospective biomarker study, TRACK-HD, and followed-up the course of HD in 117 pre-manifest gene carriers, and 116 participants with early HD1. TRACK-HD brought together experts from different disciplines from across the BRC and internationally and identified biomarkers for clinical trials1. It generated a database of brain scans that is now freely available to scientists, and demonstrated that brain changes on MRI are detectable up to 24 years before symptoms occurred. TRACK-HD has led to the development of a tool (or rating scale) that measures disease progression. BRC-funded investigators have also developed the first human test for the defective protein. The test is now validated and used as a primary endpoint in clinical trials.
Using these new biomarkers, UCLH-BRC investigators have carried out the world’s first-in-human Phase 1b/2a trial of a novel technology that corrects the genetic mutation in the huntingtin gene (sponsored by Ionis Pharmaceuticals), and demonstrated that the drug was safe and reduced the levels of the defective protein2,3. These results led to a phase 3 trial (sponsored by Roche), which was halted in March 2021 due to adverse risk/benefit profile. The advanced stage of the patients recruited into in the trial may have contributed to its failure.
The pathway from discovery to late phase trial for HD has provided crucial understanding of this incurable disease, optimum timing of intervention, and targets and biomarkers for future studies. The next generation of therapies that target the huntingtin gene is currently in development, supported by a £3.33M Wellcome Trust Collaborative Award.
1. Tabrizi SJ. Lancet Neurol. 2012; 2. Tabrizi SJ. N Engl J Med. 2019; 3. Scahill RI. Lancet Neurol. 2020.
