Laura Riggall summarises the most exciting breakthrough thus far in the search for a cure for Huntington’s disease
Huntington’s disease (HD) is a genetic neurodegenerative brain disorder. In the UK alone, around 8,500 individuals are affected, and a further 25,000 will develop HD as they age. HD is caused by a mutation: the expansion of a CAG repeat in the HTT gene. This gene codes for huntingtin, a protein vital for brain development. However, the faulty gene causes a build-up of a mutant protein, eventually causing brain cells to die.
Affected individuals experience devastating symptoms. Whilst typically manifesting at 30-40 years of age, symptoms can even begin in patients before the age of 20, and include impaired motor function such as involuntary shaking, cognitive deficits such as difficulty learning new information, and psychiatric impairments such as social withdrawal. Ultimately, patients die 10-20 years after symptoms start.
Not only are affected individuals faced with a permanently progressive decline in their ability to function, but the faulty CAG repeat region expands further with every subsequent generation. As the repeat region enlarges, symptoms manifest earlier in life. Patients therefore have to also consider the ethical implications of having children.
Unfortunately, due to the complexity of HD, there is currently no cure, and the therapeutics that are available to help alleviate symptoms are variably successful depending on the individual. In some, they offer no relief, and for those where they do, they generally only help alleviate some of the milder symptoms.
However, intensive research efforts are ongoing worldwide to try to fully understand HD pathogenesis, and develop targeted treatments to tackle the disease. In particular, UCL houses the HD Research Centre, which contains a dedicated team of clinicians and scientists deciphering the disease and testing new possible therapeutics.
Due to such monumental efforts, a highly promising breakthrough was at last announced earlier last month. IONIS-HTTRx, an experimental drug, has been tested by the HD Research Centre in collaboration with Ionis Pharmaceuticals, and its first-in-human trial has shown ground-breaking results.
After over a decade in pre-clinical development, the phase 1/2a clinical trial of IONIS-HTTRx, led by Professor Sarah Tabrizi, co-director of the HD Research Centre and IONIS-HTTRx Global Chief Investigator, began in late 2015. The worldwide trial enrolled 46 patients with early HD across nine study centres in the UK, Germany and Canada.
Patients treated with IONIS-HTTRx, which silences the faulty gene to prevent the mutant protein from being created, received four doses via injection into the cerebrospinal fluid (CSF) to allow the drug to reach the brain. As the trial progressed, the dose of the drug was increased several times. Each patient’s CSF was tested pre- and post-dose to measure the concentration of the mutant protein.
Data from the trial has confirmed that the drug is able to significantly reduce the level of the mutant huntingtin protein in the brains of patients. This also depends on the dosage of the drug delivered, confirming that any reduction in protein concentration is a direct result of the drug.
“The results of this trial are of ground-breaking importance for Huntington’s disease patients and families. For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well-tolerated.” Professor Tabrizi said in a statement. “The key now is to move quickly to a larger trial to test whether the drug slows disease progression.” Indeed, despite concerns that repeated injections of IONIS-HTTRx could cause meningitis, the drug showed no major adverse effects, supporting further testing in patients.
More advanced trials will now reveal in greater detail whether the reduction of the mutant protein can slow, or reverse, the functional decline caused by the disease. However, there are still many challenges ahead. Further clinical trials will be complex, and a phase III trial, which will reveal the true effectiveness of the drug by using different age groups, disease stages and a much larger sample size, can typically take 3-8 years to complete.
To enable further testing, Ionis’ partner, Roche, has exercised its option to license IONIS-HTTRx, assuming responsibility for further developmental, regulatory and commercialisation activities. Moreover, Ionis has announced that all patients in the completed trial will be offered a place in an open-label extension to receive IONIS-HTTRx.
Whilst being a highly exciting breakthrough towards the treatment of HD, the results of the trial also present great hope for treating other neurodegenerative diseases. Researchers may now perform trials using the same gene-silencing approach to lower the levels of mutant proteins found in similar disorders, such as beta-amyloid, a protein implicated in Alzheimer’s disease.
Overall, IONIS-HTTRx presents great new hope, not only for those currently battling the debilitating effects of HD and for those who may develop the disease, but for the many millions worldwide affected by other brain disorders. Only in time will we find out if this novel drug can be implemented on a wider level, but for now, we have good reason to be optimistic.
The results of the trial and plans for the ongoing IONIS-HTTRx programme will be presented in detail at forthcoming scientific meetings and prepared for peer-reviewed publication
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