A medical breakthrough – Experimental treatment for Huntington’s disease

By Carol Kellogg, Ph.D.

Image: Illustration of the healthy and diseased huntingtin proteins. Huntington’s disease is a severe genetic disorder in which triplet repeats in inherited DNA result in a mutant protein that aggregates in cells and causes devastating symptoms (Image Credit: National Institute of General Medical Sciences, National Institutes of Health used under a Creative Commons 3.0 license)

A recent article in the Washington Post reported the historic discovery of a drug with the potential to treat Huntington’s disease, a neurodegenerative fatal disease with no available treatment. Ionis Pharmaceuticals in California spent a decade developing the drug, and scientists at several locations in Europe and Canada conducted the research. Thirty-six subjects with Huntington’s disease were included in the Phase 1/2a trials to determine the safety and tolerability of the drug. Ionis Pharmaceuticals has now licensed the drug to its partner Roche, and that company will continue evaluating the compound. This is the first therapy designed to target the underlying cause of the disease.

What is Huntington’s disease?  Huntington’s is a disease of autosomal dominant inheritance; that is, an individual only has to inherit the mutant gene from one parent to inherit the disease (the mutant gene product has dominance over the normal gene product).  However, Huntington’s symptoms do not appear until around the third to fifth decade of life. So, an affected person spends around thirty to 50 years symptom free. Symptoms include motor, cognitive and emotional impairments, and once they appear they continually worsen over a 10-15 year period. Genes code for proteins, so persons with the mutant gene produce a mutant form of the protein huntingtin. Huntingtin is present in many neurons as well as non-neuronal cells and has been shown to serve many cellular functions.  However, the actual role of huntingtin in cells remains unclear. The mutant protein can aggregate in cells and disrupt cellular function in many ways, leading to cell death. Around 30,000 individuals are symptomatic for Huntington’s and more than 200,00 people are at risk of having inherited the mutant gene.

How Does the New Treatment Work?  The drug, called HTTRx  (HTT stands for the huntingtin protein and Rx is a symbol meaning treatment or prescription), is an antisense oligonucleotide. This means that it is a strand of chemically modified DNA designed to stick to the message molecule from the HTT gene.  DNA is a double stranded nucleotide and to produce a protein, a portion of DNA is read and translated into a message nucleotide called messenger RNA (mRNA). mRNA is than transcribed into a protein. Huntington’s disease is called a triplet repeat genetic disorder, where certain gene sequences are mistakenly repeated.  The mutation in the HTT gene was identified in 1993 and the triplet sequence can be repeated from 40 to 250 times. Since triplet sequences of DNA code for a specific amino acid in a protein, there are multiple molecules of the amino acid glutamine in mutant HTT. When the drug HTTRx reaches mRNA for HTT, it sticks to it thereby rendering the message inactive. So the treatment is like “shooting the messenger.” The difficulty in treating any disease with a drug like this is that the drug is too large to easily gain access to the brain by usual routes such as oral or intravenous administration because of brain capillary barrier mechanisms.  In the recently completed trials, the drug was administered by direct injection into the spinal fluid (intrathecal injection), a common method for treating brain cancer. Using dose escalation, scientists conducting the initial study were able to show dose-related decreases in mutant HTT in the spinal fluid.

What Will Future Trials Entail?  The need now is to test whether decreases in mutant HTT reduces symptoms and slows disease progression.  Several studies using mouse models of HD reported that deceasing levels of mutant HTT improved symptoms of the disease.  In humans it will be necessary to demonstrate whether the treatment will be effective in patients already showing symptoms or whether it will need to be given prior to developing symptoms.  If the latter is the case, patients at risk for developing the disease will need to be tested to determine whether they carry the mutant HTT gene. A test already exists, but currently only about 10 percent of individuals who are at risk choose to get tested.

What This Development Means To Patients At Risk.  Children of parents who have Huntington’s disease have a 50-50 chance of getting the disease themselves.  A genetic test became available in 1994 that lets at-risk individuals know whether they will eventually come down with the disease, but there is currently nothing that can be done for the individuals who test positive. Because of the death of nerve cells affected in Huntington’s, afflicted individuals are unable to walk, talk, or reason. The condition has been likened to having Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s disease all at the same time. The development of HTTRx  represents the first hope for individuals diagnosed with the disease.  There is considerable research needed before that hope can be realized, but at least now there is hope.

About the Author
Carol Kellogg joined Rochester NY March for Science shortly after its inception in 2017. She has a B.S. in Physical Therapy from the University of Colorado, a M.S. in Physiology from Marquette University and a Ph.D. in Physiology-Neurobiology from the University of Rochester where she was a faculty member for 39 years and is now Professor Emeritus in the Department of Brain and Cognitive Sciences. She initiated the undergraduate major in Neuroscience and maintained a research laboratory in developmental neuroscience. Carol joined the March for Science group to help counter current negative attitudes towards science and to help promote a positive role for science such as existed when she started her career.


Photo courtesy of Eric Koski

This blog is a publication of the Rochester NY March for Science. Opinions are that of the author and do not necessarily represent the views of the ROC-MFS.

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