Q: What is the difference between symptomatic and disease-modifying treatments?
A: Symptomatic treatments reduce specific symptoms such chorea or depression. They do not change the underlying course of the disease. And they may take effect quite rapidly. For example, tetrabenazine and its derivatives begin to work for chorea almost immediately. But they also lose their effectiveness when the medication is stopped. Disease-modifying treatments would actually alter the underlying progression of degeneration in the brain. Thus their effectiveness might take many months to be evident, but would be long-lasting.
A more familiar example of these distinctions might be bronchitis from a bacterial infection. Symptomatic treatments like cough suppressants would work quite quickly (minutes to hours), but would not change the course of the illness. By contrast, an antibiotic (targeted at the correct infectious organism) might take several days to work, but would cure the underlying infection.
Q: What is an example of a disease-modifying treatment for Huntington’s disease (HD)?
A: There are none so far. That’s what makes finding disease-modifying treatments the key task in HD research.
Q: What is meant by ‘Huntingtin-lowering’ or ‘Huntingtin-silencing’?
A: The mutant HD gene Huntingtin (i.e. the expanded CAG repeat) codes for a mutant Huntingtin protein, via an intermediary information-carrying molecule called messenger RNA. The mutant Huntingtin protein is believed to be the major cause of damage within neurons, leading to neurodegeneration within the striatum and other areas of the brain. New molecular biology techniques make it possible to attempt to interfere with the function of the messenger RNA molecule leading to a reduction in the levels of the mutant Huntingtin, and thus a decrease in the amount of neurodegeneration. This would, for the first time, actually modify the course of the disease. Ultimately the symptoms would be reduced as well. This overall approach is often called ‘RNA-interference’ since it interferes with the function of the messenger RNA, thus achieving ‘Huntingtin-lowering’ (or if very highly effective, ‘Huntingtin-silencing’). There are a variety of strategies being pursued to achieve this goal. Two of the major ones involve ‘antisense oligonucleotides’ or ‘viral vectors’.
Q: What are ‘antisense oligonucleotides’?
A: They are DNA molecules specially designed to target the Huntingtin messenger RNA and cause its degradation, thus achieving Huntingtin-lowering and disease-modifying therapeutics. Because they are large molecules, they do not cross the barrier around the brain so they cannot be taken by mouth or even by intravenous injection. They could be injected directly into the brain (as was done in animal studies) but the more typical strategy is to inject them via a small needle into the lower back into the fluid that surrounds the brain and spinal cord known as the cerebrospinal fluid. This is called ‘intrathecal administration’.
Q: How does this relate to the HTTRx trial by Ionis that is getting so much attention?
A: Ionis is the company that developed HTTRx which is a Huntingtin-lowering drug using intrathecal administration of an antisense oligonucleotide agent in its early trials. They were “first in human” studies designed to test different doses and show safety. They also apparently saw a reduction in mutant Huntingtin levels in the cerebrospinal fluid (CSF). This is clearly a major accomplishment. However it is important to appreciate that this was a short trial in a small number of patients, most of whom got a relatively low dose. The initial press release did not say how much reduction of mutant Huntingtin was achieved, and did not report whether or not there were any clinical changes (though in such a small short trial, one would not necessarily expect to detect clinical effect). We don’t know how well changes in huntingtin levels in the CSF would reflect huntingtin levels in the relevant parts of the brain. Most importantly, we don’t yet know whether these changes would be sufficient to cause clinical benefit. Nevertheless, this is a novel and very promising approach to the goal of disease-modifying therapy.
Q: What is the next step to find out more about this drug?
A: Larger trials now need to be conducted in many more patients with an appropriate placebo group. Ionis, the company that developed HTTRx, is a relatively small company and does not have the infrastructure to conduct a large clinical trial. So the next trials will be sponsored by Roche, a large pharmaceutical company, and are currently in the active planning phase. We are hoping that Johns Hopkins, building on our participation in the ‘HDClarity’ study, will be a site in this larger trial of HTTRx, to see if it can really modify the underlying disease, and thus slow the clinical progression.
Q: What are the “HDClarity” and “ENROLL-HD” studies?
A: HDClarity is a research study currently underway here at Hopkins in which cerebrospinal fluid (CSF) is collected to study the progression of HD using a routine procedure called a lumbar puncture or spinal tap, which takes about 30 minutes. The goal is to quantify levels of mutant Huntingtin and other biomarkers. A biomarker is anything that can be measured, such as chemical substances in the CSF that reflect neuronal injury, in order to help us understand HD.
Biomarkers may help guide future research studies and clinical trials, as well as help us better understand who will most likely benefit from a particular treatment. CSF can be used to provide information about the brain and nervous system that is impossible to obtain in any other way. Individuals with a positive or negative HD genetic test status, or family not related through blood (i.e. spouses and partners) may participate.
We are actively enrolling for the HDClarity study, and were the first US site (and as of December 2017 the only U.S. site actively enrolling). Participants must be part of the ongoing observational study, called ENROLL-HD, which just involves tracking routing motor, cognitive and emotional changes over time.