Huntington’s Staging System Might ‘Revolutionize’ Trials, Therapy Work
The international Huntington’s Disease Regulatory Science Consortium (HD-RSC) developed a biological definition of Huntington’s disease (HD) and a staging system that, for the first time, covers the entire disease course.
The development and validation processes of the new framework, called the Huntington’s Disease Integrated Staging System (HD-ISS), were detailed in the study “A biological classification of Huntington’s disease: the Integrated Staging System,” published in the journal The Lancet Neurology.
“HD families have long known that signs and symptoms begin decades before the classical motor onset diagnosis that occurs late in the disease course,” Sarah Tabrizi, PhD, the study’s co-first author with the Huntington’s Disease Centre, Queen Square Institute of Neurology, and the UK Dementia Research Institute, all at University College London (UCL), said in a university press release.
Tool to transform therapy development, patient trials
HD-ISS “will revolutionize our ability to evaluate novel disease-modifying therapeutics much earlier in the disease course, when therapies will likely have the best chance of slowing disease progression and providing clinical benefit,” Tabrizi added “Ideally, we’d like to delay or prevent neurodegeneration while function is still intact, giving people with HD many more years without impairment.”
It also has “the potential to transform how HD clinical research is conducted, enabling study of the earliest disease phases and planning of preventive clinical trials, as well as facilitating data aggregation and sharing,” said Cristina Sampaio, MD, PhD, a study author.
Sampaio is the chief clinical officer of the CHDI Foundation, which together with the Critical Path Institute (C-Path) created the HD-RSC.
Huntington’s is caused by excessive repeats of a portion of DNA, called CAG triplets, within the HTT gene. Healthy people normally have between 10 and 35 CAG repeats, but those with Huntington’s may have 36 to 120 repeats, with longer regions tied to early disease onset.
Excessive CAG repeats result in the production of an abnormal and toxic version of the huntingtin protein that ultimately leads to progressive neurodegeneration.
“The current research paradigm for Huntington’s disease is based on participants with overt clinical [symptoms] and does not address its [underlying mechanisms] nor the biomarker changes that can precede by decades the functional decline,” the researchers wrote.
To address this, the HD-RSC “generated a new research framework to standardize clinical research and enable interventional studies earlier in the disease course,” they added.
It marks the first time a staging system has been developed for a genetic neurological condition.
The consortium’s Research Science Forum working group — formed by representatives from the academia, clinic, and industry involved in Huntingnton’s therapy development — served as an expert panel to agree on the questions to be systematically investigated, examine scientific evidence, and achieve consensus on conclusions.
Conclusions were reviewed and approved by the HD-RSC, which at the time included 24 pharma and biotech companies, eight nonprofit research or advocacy organizations, five academic institutions, and 19 individual scientific advisers.
Informal feedback on the HD-ISS was sought from patients through the Huntington’s disease Coalition for Patient Engagement and from regulatory agency partners such as the U.S. Food and Drug Administration.
“This research required the selflessness and dedication of thousands of research participants from HD families, to whom we are immensely grateful,” Tabrizi said.
4 stages of Huntington’s progression
The HD-ISS includes a biological research definition of Huntington’s and evidence-based staging centered on biological, clinical, and functional assessments.
Based on previous data, Huntington’s was defined by the presence of either 40 or more CAG repeats in the HTT gene, or 36 or more repeats and the presence of a disease-specific biomarker or a set of disease-specific clinical signs or symptoms.
Since further research is needed to establish disease-specific biomarkers or symptoms that strongly predict disease development in people with 36–39 CAG repeats, the staging system focuses only on those with 40 or more repeats.
HD-ISS staging criteria divides people carrying at least 40 CAG repeats into four stages based on thresholds of stage-specific landmark assessments.
Those without any detectable disease-associated biomarker, sign or symptom, or functional change will be classified as being in Stage 0 of the disease, while those with a disease-specific biomarker of neurodegeneration — MRI-assessed shrinkage of two brain regions — will be at Stage 1.
Stage 2 begins with the additional presentation of motor or cognitive manifestations of Huntington’s, as assessed with the Total Motor Score and the Symbol Digit Modalities Test, respectively.
People presenting not only disease-specific biomarkers and symptoms, but also a decline in functional ability, such as difficulties performing activities of daily living, will be classified as being at Stage 3. This functional decline will be measured with the Independence Scale and the Total Functional Capacity scale, and classified as mild, moderate, or severe depending on the degree of disability.
While “the HD-ISS stages are not meant to be the sole inclusion criteria in clinical research,” the researchers wrote, “terms such as manifest, premanifest, and prodromal should be replaced with the language of the HD-ISS.”
“We anticipate that the HD-ISS could be an important foundation on which to build regulatory strategies and guidance on disease-modifying (and potentially preventive) Huntington’s disease treatments,” the team wrote.
“This is a positive and powerful development that brings the lived experience of people with HD to the heart of research and provides a path forward for people earlier in their HD journey to be a part of clinical research,” said Louise Vetter, president and CEO of the Huntington’s Disease Society of America.
“The overwhelming response from HD families has been ‘What took so long?’”
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