New system that defines Huntington’s disease will ‘revolutionize’ drug trials

A new staging framework which assesses the progression of Huntington’s disease (HD), similar to the way cancer is staged from 0 to 4, was developed by scientists at University College London (UCL) as part of an international consortium ; this “significant” step paves the way for clinical trials of drugs in the earliest phase of the disease.

HD is a progressive and devastating genetic (inherited) neurodegenerative disease, which affects around one in 10,000 people in the UK.

There is currently no approved treatment that can slow the progression of the disease. The Huntington’s Disease Integrated Staging System (HD-ISS) groups people with HD (PwHD) based on their underlying biological (including genetic), clinical, and functional characteristics. This is the first time that a staging system has been developed for a genetic neurological disease.

Posted in The Lancet Neurology, the new evidence-based framework also includes criteria to biologically define the stages of HD across the entire disease trajectory from birth, something that has never been done before.

The HD-ISS staging criteria cover the full spectrum of the disease, beginning with stage 0 (individuals carrying the HD genetic mutation without any detectable pathological changes), stage 1 (later progression marked by measurable indicators of underlying pathophysiology via biomarkers), stage 2 (a detectable clinical phenotype), and finally stage 3 (decline of function).

At this point, the HD-ISS is for research use only, not for clinical practice.

First author Professor Sarah Tabrizi (UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL) said: “HD families have long known that signs and symptoms begin decades before the diagnosis of classic motor onset which occurs late. in the progression of the disease.

“We have developed the HD-ISS using state-of-the-art evidence-based methodology and it will revolutionize our ability to evaluate new disease-modifying therapies much earlier in the course of the disease, when therapies are likely to have the best chances of slowing disease progression and providing clinical benefit.

“This research required the selflessness and dedication of thousands of research participants from HD families, to whom we are extremely grateful.

“Ultimately, our goal is to provide treatments at the right time to effectively treat this disease. Ideally, we would like to delay or prevent neurodegeneration while function is still intact, giving people with HD many more years without impairment. The HD-ISS is an important tool that will allow us to do this as the therapeutics emerge.”

The HD-ISS defines groups of PwHD with similar prognostic characteristics for research purposes and will facilitate the comparison of data between different trials and studies, accelerating drug development and facilitating communication between different stakeholders, from HD families to health policy professionals.

Importantly, this new biological research definition of HD will allow new therapies to be evaluated in people in the very early stages of the disease, before they show overt clinical signs; this will likely provide the best chance of significantly slowing disease progression and provide the disabled with the greatest clinical benefit.

Cristina Sampaio, MD, PhD, Clinical Director at CHDI Management/CHDI Foundation, said, “As a validated staging system, the HD-ISS has the potential to transform the way clinical HD research is conducted, enabling the study of the early stages of disease and the planning of preventive clinical trials, as well as the facilitation of data aggregation and sharing.

“For HD families, it should be emphasized that this is for research purposes only, it will not affect their clinical care.”

The current clinical diagnosis of HD is based on the observation of established clinical signs (mainly involuntary motor signs, but also cognitive disorders and behavioral changes) which appear late in the course of the disease. This diagnostic approach was developed before the discovery of the Huntington gene and the resulting genetic test for CAG expansion – the DNA mutation that causes disease – and before current understanding of disease-related pathobiological changes. which develop several decades before these observable clinical signs. panels.

The stage of disease preceding this current diagnostic stage has been variously described as “presymptomatic”, “pre-manifested” or “prodromal”, ill-defined terms that make it difficult to compare data and results between trials and studies. .

Emily Turner, PhD, Executive Director of the Huntington’s Disease Regulatory Science Consortium (HD-RSC) at the Critical Path Institute (C-Path), said, “The HD-ISS truly represents a pivotal and collaborative moment in clinical disease research. of Huntington, and the Critical Path Institute is proud to have helped facilitate the development of this much needed staging system.

Louise Vetter, President and CEO of the Huntington’s Disease Society of America (HDSA), said, “This is a positive and powerful development that puts the lived experience of people with HD at the heart of the researches and paves the way for people earlier in life. their HD journey to be part of clinical research. The overwhelming response from HD families was “What took so long?”

– This press release was originally published on the University College London website