BSc (Hons) MBChB (Hons) FRCP PhD FMedSci
Professor of Clinical Neurology
This site aims to bring together information about our research projects in Huntington’s disease (HD) for patients, family members and health professionals.
Through the Huntington’s Disease Multidisciplinary Clinic of the National Hospital for Neurology and Neurosurgery, we offer expert care and involvement in cutting-edge research, including clinical trials and work to understand HD and develop new treatments.
Our group is the largest and most productive clinically-focused HD research group in the UK.
We are delighted to accept donations to support our research, to help us understand and treat Huntington’s disease. Please donate via our UCL fundraising page.
We are pleased to announce recruitment is now open for HD-CSF, a major new study of cerebrospinal fluid to help understand and treat Huntington’s disease. For full details click here.
Trial of innovative drug, developed by Isis Pharmaceuticals, aims to reduce production of the toxic protein that causes devastating brain disease
The first few patients have received doses of an experimental drug for Huntington’s disease, it was announced today.
The trial aims to test the safety of an experimental drug known as ISIS-HTTRx, discovered and developed by Isis Pharmaceuticals. Administered by injection into spinal fluid to improve its delivery to the brain, the drug is the first tested in patients that targets the known cause of the disease: a toxic protein called mutant huntingtin which slowly damages and kills neurons, leading to the progressive and ultimately fatal decline in mental and physical abilities that is the devastating hallmark of Huntington’s disease.
The huntingtin gene and its lethal protein product have been the focus of intense research across the world since their discovery in 1993. ‘Gene silencing’ drugs, also known as ‘antisense’ drugs, are designed to reduce production of a chosen protein by attaching to the mRNA ‘message molecule’ that’s made whenever a gene is activated. ISIS-HTTRx targets the huntingtin message molecule, telling the cell to dispose of it, thereby reducing production of the mutant huntingtin protein.
There are no treatments to prevent, slow or cure Huntington’s. RNA-targeting antisense drugs, like ISIS-HTTRx, that lower huntingtin production are widely considered the most promising therapeutic strategy currently under investigation. Isis’s Huntington’s disease therapeutics underwent over a decade of refinement and preclinical testing before human trials could begin. The first Phase 1/2a trial is focused principally on safety, using slowly increasing doses of ISIS-HTTRx with careful monitoring of patient wellbeing, scans and laboratory parameters. In addition, the researchers will be looking for chemical signs that the drug is having the desired effect – by measuring the level of mutant huntingtin protein in the cerebrospinal fluid using a newly developed assay.
The trial is set to recruit patients with very early symptoms of Huntington’s from six centres in Europe and Canada. Prof Sarah Tabrizi, director of the Huntington’s Disease Centre at University College London’s Institute of Neurology, is the global chief clinical investigator of the trial. “I’m thrilled that this antisense drug has now been safely administered to the first patients. Families ravaged by Huntington’s disease have been waiting for this milestone for decades. I look forward to ensuring the smooth running of this first trial and hopefully seeing ISIS-HTTRx through to efficacy testing and licensing,” said Prof Tabrizi.
Isis Pharmaceuticals has partnered with Roche to develop ISIS-HTTRx to treat Huntington’s disease. C. Frank Bennett, Ph.D., senior vice president of research at Isis Pharmaceuticals, said, “Antisense drugs have great potential for many neurodegenerative diseases because they can be tailored to modify the production of any target protein. Huntington’s is ideally suited to this innovative therapeutic technology because it comes with genetic certainty: everyone with the mutant gene will get the disease at some point. We designed ISIS-HTTRx to target the huntingtin gene and reduce the production of huntingtin protein, which is the known cause of the disease. This approach has the potential to prevent or slow the progression of this disease. If this first-in-human trial proves the drug is safe, we look forward to continuing our successful partnership with Roche to bring the drug to market.”
At UCL, the trial is hosted in the new Leonard Wolfson Experimental Neurology Centre, a custom-built centre designed to accelerate innovative treatments for neurodegenerative diseases, headed by Prof Vincenzo Libri. The administration of the first doses of ISIS-HTT-Rx marks the Centre’s first use as a phase 1 ‘first into human’ trial facility, as well as the first time that an experimental drug has been given by spinal injection in the 156-year history of the National Hospital for Neurology and Neurosurgery, part of University College London Hospitals (UCLH) NHS Foundation Trust. Crucial support for this important achievement came from a groundbreaking partnership with the Clinical Trials Pharmacy at nearby Great Ormond Street Hospital (GOSH) where the ISIS-HTT-Rx is prepared for administration. The trial also demonstrates the value of successful collaboration between NHS and academic infrastructures in the form of the National Institute for Health Research (NIHR) UCL/UCLH Biomedical Research Centre.
Cath Stanley, Chief Executive of the Huntington’s Disease Association of England and Wales, welcomed the news that the first doses of ISIS-HTTRx had been given to Huntington’s patients. “As well as being desperate for good news, the Huntington’s community is uniquely well-informed and engaged with progress in research across the world,” she said. “RNA-targeting approaches are especially exciting because they tackle the problem at its source – the production of the mutant huntingtin protein. The ISIS-HTTRx trial has been eagerly awaited for many years and we hope that the news from the trial continues to be positive.”
A new measure has been developed which can explicitly characterise compensation in Huntington’s disease (HD) gene-carriers prior to clinical diagnosis. Publishing in EBioMedicine, the research team working on the study hope that identifying patterns of compensation in preclinical HD will not only improve understanding of neural mechanisms underlying HD pathology, but also provide potential targets that can be used in the testing of HD therapeutics.
HD is a neurodegenerative disease and despite considerable neuronal loss, preclinical HD gene-carriers are able to maintain normal behavior during many motor and cognitive tasks. This suggests that some form of compensation is taking place which enables those in the early stages of the disease to function normally. However, until now, there has been no experimentally-testable model of compensation to investigate this.
The international team of scientists from the Department of Neurodegenerative Disease and the Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, UCL Institute of Cognitive Neuroscience, Albert Ludwigs University of Freiburg, University Hospital Salpêtrière Paris, University of Leiden, University of British Columbia, University of Ulm, University of Iowa, and Monash University Melbourne and the CHDI Foundation have developed a new model which uses functional and structural Magnetic Resonance Imaging (MRI) to investigate potential compensatory associations between behaviour and brain activity in preclinical HD patients. Using variability in levels of brain atrophy to mark disease severity, the research team have shown that in those HD gene-carriers with the most significant neuronal loss there is localised compensation in the right hemisphere during cognitive processing, while comparable function in the left hemisphere appears to deteriorate.
“In demonstrating hemisphere-specific compensation in preclinical HD gene-carriers, we have provided potential targets for the future planned testing of disease modifying agents in the preclinical phases of HD where it may be important to monitor for preservation of compensatory activity.” said Prof Sarah Tabrizi of UCL Institute of Neurology.
Furthermore, as HD is caused by a single gene mutation and fully heritable, it is an ideal model for studying not only the earliest stages of HD, but neurodegeneration generally, as it possible to predict who will develop the disease many years before symptom onset.
“By using this model we can gain insight into the more common protein-misfolding neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, which are largely sporadic and are therefore much more challenging to study in the preclinical phases.”
A new paper by Dr Ed Wild in collaboration with scientists from University College London, IRBM Proidis, University of British Columbia, University of Iowa , The University of Gothenburg and CHDI foundation has just been published in The Journal of Clinical Investigation.
The paper describes a new ultra sensitive test that has been able to measure for the first time the build-up of a harmful mutant protein in the nervous system of patients during the progression of Huntington’s disease. The test is able to detect single molecules of mutant huntingtin in the cerebrospinal fluid of HD patients, including people who carry the gene but have not yet developed symptoms.
“We think the mutant huntingtin is being released into the CSF from the very brain cells it is killing,” said Dr Edward Wild of UCL Institute of Neurology. “It may be a smoking gun that reflects the harm the protein is doing in the living human nervous system.”
As well as detecting the protein for the first time, the researchers found that the level of mutant huntingtin was higher in volunteers with more advanced disease and the concentration of mutant huntingtin predicted the severity of movement and cognitive problems in patients.
2015 will see the start of the first human clinical trial of a gene silencing or huntingtin-lowering drug, which specifically aims to reduce production of mutant huntingtin in the brains of HD patients. Being able to detect and measure the amount of mutant huntingtin present in the nervous system will be a valuable way of seeing whether the gene-silencing drug is hitting its target and has the intended effect, lowering the amount of disease causing mHTT protein. Meanwhile, this new technique will be an invaluable tool to help researchers study the effects of this devastating disease in the living nervous system.
At last month’s European Huntington’s Disease Network meeting, Prof Sarah Tabrizi proudly announced that, in partnership with Isis Pharmaceuticals, Inc, she will be the lead investigator of the world’s first clinical trial of a huntingtin lowering (sometimes called ‘gene silencing’) drug for Huntington’s disease.
Called Isis HTT-Rx, the drug is an antisense oligonucleotide or ASO that has shown success in reducing production of the harmful mutant huntingtin protein and improving symptoms in animal models of HD. The multi-centre, multi-national trial will investigate the safety of increasing dose levels of Isis HTT-Rx and will be led by Prof Tabrizi and her team at UCL Institute of Neurology.
Watch Prof Tabrizi’s presentation on Isis HTT-Rx and the clinical trial:
Later, Dr Ed Wild and Dr Jeff Carroll interviewed Prof Tabrizi to find out more about how the trial will work and what it means for patients and families: