A Potential New Avenue for Huntington’s Disease Treatment

by Lauren Lin

Huntington’s disease (HD) is a fatal neurodegenerative disease that has symptoms such as chorea (jerky, involuntary movements), loss of coordination, and difficulties with walking, talking, swallowing, focusing, recalling memories, and making decisions. People with HD may also experience increased anxiety, depression, aggression, and impulse control issues. As a neurodegenerative disease, the symptoms begin with subtle issues associated with the previously mentioned symptoms and become more severe over time.

HD is one of the few neurodegenerative diseases that has a clear genetic component. It was identified in 1993 that HD is caused by a mutation in the gene found on chromosome 4 that codes for the huntingtin protein (the Htt gene). Although CAG repeats are found in healthy individuals, individuals with HD have very high numbers of CAG repeats in the Htt gene, and more repeats are associated with more serious manifestations of the disease. The huntingtin gene is dominant, meaning that individuals only need one copy of it from their mother or father to have HD. Therefore, children of parents with HD have a 50% chance of inheriting the disease. Symptoms usually appear between the ages of 35 to 55, but individuals may have symptoms starting before 20 (called Juvenile HD) or in late adulthood (Late Onset HD).

The function of the huntingtin protein in healthy individuals is still unclear, but the protein seems to play a role in the function of nerve cells since huntingtin appears to interact with proteins that only exist in the brain. The mutated huntingtin gene leads to abnormal aggregates of huntingtin protein fragments in the brain called neuronal inclusions. The basal ganglia, a brain area that is involved in movement coordination, seems to be the most affected by neuronal inclusions. However, the cerebral cortex, which plays a role in cognitive processes like attention, is also vulnerable to the effects of the huntingtin protein. The symptoms related to the cerebral cortex (i.e. cognitive difficulties) show up later than motor difficulties, which are associated with effects of the abnormal huntingtin protein on the basal ganglia.     

Currently, there are no drugs that can prevent or slow down the progression of Huntington's disease, but drugs are given to people with HD to help manage their symptoms. For example, some antipsychotic drugs such as haloperidol may be given to patients with HD to help with hallucinations (which sometimes individuals with HD experience), violent outbursts, and chorea. Antidepressant and anxiolytic (anti-anxiety) drugs are also sometimes given to help with the psychiatric symptoms that individuals with HD may have.

However, many researchers are investigating new possible treatments for Huntington’s Disease, and a new gene-silencing treatment has been found to have potential in treating HD. A new drug called Ionix-HTTRx is an antisense drug that contains part of a strand of synthetic oligonucleotides that selectively binds to messenger RNA (mRNA) to block translation of all huntingtin protein. The drug is injected into the fluid around the spinal cord, which is then carried to the brain in the cerebrospinal fluid.

This month, Ionix Pharmaceuticals reported their findings from a phase 1 trial that included 46 patients aged 25 to 65 from Canada and Europe. The study was 13 weeks long, during which participants were assigned randomly to be injected with one of five possible dosages of IONIS-HTTRx or a placebo. One injection was given each month, and at the end of the study, the participants who received the highest two doses of IONIS-HTTRx had about a 40% reduction in mutant huntingtin (mHTT) levels in their cerebral spinal fluid. The researchers predict that the decreases in mHTT in the cerebral spinal fluid correspond to a 55-85% reduction of mHTT levels in the brain cortex, which may lead to clinically significant results. However, more research trials need to be done with more patients and for longer periods of time to provide a better understanding of whether the drug is truly effective in reducing the levels of huntingtin protein in the brain and helping with HD symptoms. There are plans to conduct more trials beginning later in 2018 or early 2019.
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Since only one research trial has been done with Ionix-HTTRx and the trial had a very small sample and lasted for a short time, researchers and healthcare professionals do not have enough evidence to support the effectiveness of the drug. That being said, the potential for a drug to decrease the amount of harmful huntingtin protein fragments in the brain brings with it a lot of optimism and hope that we may be able to better treat Huntington’s disease.