Slowing the Progression of Huntington’s disease
With recent advancements in the field, there has been a greater understanding of neurodegenerative disorders such as Huntington's disease. Huntington's disease is a hereditary, neurodegenerative disorder which has physical and cognitive symptoms.1 It is a fatal disorder, with a poor prognosis due to the numerous complications including pneumonia and heart failure.1 Huntington’s disease affects nearly every aspect of the patient's life, from cognitive to physical functions. Patients often suffer from depression, irritability, and various other symptoms that inevitably result in progressive dementia.2 Patients are also plagued with involuntary jerky writhing movements called chorea and an overall impairment of voluntary movements. The slow decline individuals experience as a result of Huntington's usually occurs in middle adulthood. As the disease progresses, symptoms intensify, and the disease often becomes fatal 15-20 years after its initial onset.2 More than 21,000 Canadians currently have the disorder or carry the single-gene mutation, and individuals with the disease have a 50% chance of passing it onto their children.1 A major focus of research on Huntington's is understanding the toxicity of mutant huntingin protein and its effect on brain cells in order to develop potential drugs for counteracting its effects.
Huntington’s disease is caused by the mutation in the HTT gene responsible for producing the protein huntingtin.3 Although the exact function of this protein is currently unknown, it is assumed to play an important role in regulating nerve cells (neurons) in the brain.3 In Huntington’s patients, a specific part of the sequence is redundant at the beginning of the gene, causing cells to manufacture a harmful mutant huntingtin.3 The mutant huntingtin causes the caudate and cerebral cortex to degenerate.3 The dysfunction and necrosis of neurons in these specific areas of the brain underlie the signs and symptoms of Huntington's disease.
Current treatment options for Huntington’s disease focus on symptom management. Xenazine (tetrabenazine) is a dopamine-depleting agent that is specifically approved for Huntington’s cholera. However, it has a risk of potentially serious adverse effects such as parkinsonism, depression and acute akathisia.4 Physical therapy can also help maintain normal mobility and prevent falls. Further speech therapy can also be implemented to address speech impediments caused by deficiencies in controlling the muscles of the mouth and throat.5 Psychiatric symptoms are managed using antidepressants, antipsychotics, and mood-stabilizing medications. 5 There is currently no treatment option allowing patients to stop or reverse the progression of Huntington's disease; however, researchers are currently examining the mechanism of Huntington’s in order to find viable therapeutic targets.
There are many lines of promising research. However, one breakthrough was a set of clinical trials demonstrating that IONIS-HTTRx is effective in slowing the progression of the disease.6 One of the very first patients, Michelle Dardengo, was treated in Vancouver in September 2015.7 Nearly a decade after her initial diagnosis of Huntington’s, Dardengo’s physician, a Huntington disease researcher at the University of British Columbia, informed her of a clinical trial for a novel treatment made by Ionis Pharmaceuticals.7 This drug which was the product of 25 years of research, was “an antisense molecule—a short stretch of synthetic DNA tailor-made to block the production of the huntingtin protein.” 7 After starting the treatment, “[Dardengo] and her family believe that the deterioration of her memory has stabilized.”7
The drug IONIS-HTTRx is a type of antisense oligonucleotide (ASO) which works by destroying the RNA of the HTT gene, preventing the mutant huntingtin protein from being made.8 IONIS-HTTRx also offers a unique approach to treat all patients with HD, irrespective of their individual HTT mutations.8 In the preliminary study, 46 people with early-stageearly stage HD were treated with four intrathecal injections of 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg of RG6042 or placebo, administered monthly. Significant, dose-dependent reductions of mHTT were observed in cerebrospinal fluid (CSF) of treated participants with mHTT reductions of up to an estimated 60% and mean reductions of approximately 40% in CSF observed at the two highest doses, 90 mg (p<0.01) data-preserve-html-node="true" and 120 mg (p<0.01).9 These clinical results demonstrate the approach of targeting the production mutant huntingtin can significantly reduce the underlying cause of this disease. No serious adverse events (AEs) were reported in the study’s participants and most AEs were mild and considered to be unrelated to RG6042.9 No enrolled patients withdrew from the study, and an open-label extension study for participants is ongoing.9 These preliminary trials testing the efficacy of IONIS-HTTRx were the first to show that levels of toxic mutant huntingtin protein can be lowered in those with Huntington’s disease, and show significant promise in improving the clinical prognosis of Huntington’s disease.
1. Huntington Society of Canada. https://www.huntingtonsociety.ca/learn-about-hd/what-is-huntingtons/
2. Frank S. Treatment of Huntington's disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. https://www.ncbi.nlm.nih.gov/pubmed/24366610. Published January 2014.
3. Zheng Z, Diamond MI. Huntington Disease and the Huntingtin Protein. Progress in Molecular Biology and Translational Science Molecular Biology of Neurodegenerative Diseases. 2012:189-214. doi:10.1016/b978-0-12-385883-2.00010-2.
4. Paleacu D. Neuropsychiatric Disease and Treatment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656291/. Published October 2007.
5. Treatments for Huntington's disease. Huntington's Disease News. https://huntingtonsdiseasenews.com/treatments/.
6. Figueiredo M. IONIS-HTTRx Shows Promising Results in Huntington's Disease Trial. Huntington's Disease News. https://huntingtonsdiseasenews.com/2018/03/08/ionis-httrx-shows-promising-results-in-huntingtons-disease-clinical-trial/. Published March 8, 2018.
7. WadmanAug M, StoneOct R, CleryOct D, KaiserOct J, Mervis J, You J. 'I feel so much hope'-Is a new drug keeping this woman's deadly Huntington disease at bay? Science AAAS. http://www.sciencemag.org/news/2018/08/i-feel-so-much-hope-new-drug-keeping-woman-s-deadly-huntington-disease-bay. Published August 27, 2018.
8. New Data from IONIS-HTT Rx Phase 1/2 Study Demonstrates Correlation Between Reduction of Disease-causing Protein and Improvement in Clinical Measures of Huntington's Disease. Ionis Pharmaceuticals, Inc. http://ir.ionispharma.com/news-releases/news-release-details/new-data-ionis-htt-rx-phase-12-study-demonstrates-correlation.
9. Figueiredo M. IONIS-HTTRx Shows Promising Results in Huntington's Disease Trial. Huntington's Disease News. https://huntingtonsdiseasenews.com/2018/03/08/ionis-httrx-shows-promising-results-in-huntingtons-disease-clinical-trial/. Published March 8, 2018
Cite This Article:
Kim MJ. Chan G. Slowing the Progression of Huntington's disease. Illustrated by Ala K. Rare Disease Review. November 2019. DOI:10.13140/RG.2.2.31084.31367.