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Ground-breaking drug lowers deadly Huntington’s disease protein for the first time

The first drug targeting the known cause of the fatal brain disorder Huntington’s disease has successfully lowered the level of the harmful huntingtin protein in the nervous system, in a trial led by BRC-supported researchers. 

The drug (IONIS-HTTRx) targets the product of the HTT gene, including the mutated form that is responsible for damaging neurons. By reducing the production of the mutant huntingtin protein in people with Huntington’s disease, the drug has the potential to alter the course of the disease.

Up until this trial, which showed the drug to be safe and well-tolerated in humans and is a likely precursor for further larger trials, no therapy of this type had been tested in patients. There are no disease-modifying treatments currently available, and the disease is incurable. 

The global study led by Professor Sarah Tabrizi, of UCL/UCLH Huntington’s Disease Centre and which was carried out at the Leonard Wolfson Experimental Neurology Centre, shows results that pave the way for the first potential disease-modifying treatment for patients suffering from the neurodegenerative disorder. This study is the first time that the huntingtin protein has been lowered in the nervous system. The Leonard Woldson Experimental Neurology Centre is part of the NIHR UCLH Clinical Research Facility and is supported by our BRC. 

The drug is a chemically modified single strand of DNA that destroys the chemical message produced by the HTT gene, a molecule called “messenger RNA” that carries the instructions for making the lethal huntingtin protein. The drug is an antisense oligonucleotide (ASO), designed specifically to trigger the breakdown of huntingtin messenger RNA.  By destroying the huntingtin messenger RNA, the ASO prevents the huntingtin protein from being made.  In the trial that just completed, the investigators found that giving a small amount of ASO resulted in a small suppression of mutant huntingtin production, while giving a larger amount of ASO resulted in a larger suppression of mutant huntingtin production.  Altering the amount of mutant huntingtin in the human nervous system is the critical first step toward developing a drug that can change the course of the disease.

Professor Sarah Tabrizi, also IONIS-HTTRX Global Chief Investigator, said: “The results of this trial are of ground-breaking importance for Huntington’s disease patients and families. The key now is to move quickly to a larger trial to test whether the ASO slows disease progression.”

Results of this trial, sponsored by Ions Pharmaceuticals, will be presented at forthcoming meetings to further develop the future prospects of this revolutionary drug. Roche has licensed the drug from Ionis and will now be responsible for further studies, global development and commercialization of IONIS-HTTRx.

Huntington’s is a fatal genetic disease that affects 100,000 individuals in the UK alone. Patients usually die within 20 years, from first sign of symptoms. As a single genetic mutation, children who have a parent carrier have a 50% chance of inheriting the disease.