Hunting Down Huntington
(December 9th, 2015) At present, there are no treatments available to cure or slow the progression of the neurodegenerative genetic disorder, Huntington’s Disease (HD). However, a new gene-silencing drug is currently being trialled and may soon change this situation.
First described in the 19th century, Huntington’s Disease has a worldwide prevalence of 5-10 cases per 100,000 persons. The hereditary disease comes with a range of symptoms, including impaired gait, balance, difficulty in learning new information and insomnia. At the base of the neurodegenerative disorder is the mutated huntingtin gene. Currently, there’s no cure for HD; patients can only reduce the severity of the symptoms.
But in October, University College London (UCL) announced, they treated their first HD patient with a gene-silencing drug developed by ISIS-pharmaceuticals. Edward Wild, Clinician Scientist at UCL, is involved in the trial, led by Sarah Tabrizi. He explains the backgrounds: “HD, despite being classed as a rare disease, is one of the commonest brain diseases. It is autosomal dominant and fully penetrant, which means that all children of an affected parent have a 50% chance of getting the disease, since if they get one copy of the mutant gene they are destined to get the disease. The mutation responsible for the disease has been known for 22 years – a CAG repeat expansion within the huntingtin gene. People with up to 26 repeats will not get the disease, whereas people with over 40 repeats will definitely get the disease, with onset typically being seen in the 30s or 40s, with more than 60 repeats typically being associated with juvenile onset, which is seen on around 10% of patients. Since the cause is known, and always the same, HD represents a good model neurodegerative disease to test potential treatments.”
Although huntingtin is expressed throughout the body, the expression is particularly high in the brain. Cells in the basal ganglia and parts of the cortex of the brain are very sensitive to the effects of the abnormal huntingtin, which accumulates over time, causing them function poorly and eventually die, which is associated with shrinkage of the brain. According to Wild, “the behavioural changes are usually the most shocking and difficult for the family to deal with - such as obsessive compulsive behaviour, and often a complete change in personality”.
The gene-silencing drug, ISIS-HTTRx, has been specifically designed to treat HD, by reducing levels of huntingtin expression. The drug is an antisense oligonucleotide, an artificial strand of DNA, which binds the mRNA, resulting in its degradation and preventing synthesis of the huntingtin protein. Wild noted that “the drug is non-selective and will reduce the level of both the mutant and wild type form of the protein, of which the patient will usually have a gene for each, as this will allow one drug to be used universally in all patients. Previous animal studies have shown that the reduction in both forms of the protein is both safe and effective, and hopefully in this new trail we will see the same for patients”.
The trial will recruit 36 patients with early stage HD to be treated at UCL and Manchester in the UK, as well as two locations in Germany and two in the USA. Wild stated “the reason for recruiting early stage HD patients is that it will be very easy to see any potential worsening of the condition. The focus of this 1a/2a trial is primarily to assess safety, although we will also check the cerebrospinal fluid to assess whether we are effectively able to reduce huntingtin protein levels, along with reduction in things such as inflammatory markers and markers of neuronal cell death”. Patients will receive four increasing doses of the drug, one month apart, with the hope of lowering the huntingtin protein levels by 50%. Previous pre-clinical work has shown that this reduction allows the brain to clear up some of the mutant huntingtin that has accumulated.
Wild told Lab Times, “Over the last two years, we have seen several exciting advances in the field. Although the ultimate cause of HD has been known for 22 years, a study published this year, successfully identified two modifiers on chromosomes 8 and 15, which likely include DNA repair genes that hasten or delay disease onset by up to six years. Additionally, the effective evaluation of treatment success has been enabled by our development of new assays to measure levels of cerebrospinal fluid biomarkers. At UCL, we are investigating two other drugs in addition to ISIS-HTTRx; Laquinimod, an existing anti-inflammatory drug used to dampen the activity of the body’s immune system, which has been found to be hyperactive in HD; and a Pfizer drug related to Viagra that may help neurons to communicate more effectively. Other treatments such as CRISPR gene editing of the huntingtin gene being investigated by other groups may also prove effective. Hopefully, HD will be treatable in the near future.”