When we read medical journals or magazines about research on certain diseases, most articles that appear on the front pages cover health issues that affect a large part of the population. Although it is practical to see medical news that is relevant to most people, sometimes it is both informative and useful to evaluate potential treatments for less common diseases. One example of a rare disease that has pioneering contemporary clinical research is Huntington’s Disease. Huntington’s Disease (HD), affecting about three people per every 100,000 worldwide, is a devastating and fatal neurodegenerative disease characterized by a gradual decline in cognitive function and motor coordination (1). HD patients progressively lose cognitive and motor skills over the course of about 20 years until, in late stage HD, they can no longer care for themselves. In the past, HD families have had to care for HD patients with the knowledge that there are no treatments beyond those for motor symptoms of the disease (1). However, with the advent of an exciting upshot in promising clinical studies, there is much more hope to achieve a treatment for HD. Currently, there are a variety of promising clinical trials relating to HD, which all have strong implications for potentially slowing, halting or even reversing cognitive decline. In this article, I will explore the differences between five promising clinical trials that attempt to reduce mutant Huntingtin protein (mHTT) in the brain as to slow the progression of HD.
Ionis Pharmaceuticals and Roche are running the biggest ongoing huntingtin-lowering studies. Huntingtin is a protein that plays an important role related to the development of the brain’s neurons; a mutated version called mHTT has a causal impact on HD progression (1). Ionis and Roche have put together two Phase 3 trials called GENERATION-HD1 (a double-blinded study) and Natural History (a non-drug observational study) on a promising huntingtin lowering drug, IONIS-HTTRx or RG6042 (2). A Phase 3 clinical trial evaluates an experimental drug on a large population for an extended period of time to determine its clinical benefit(s) (3). Roche’s Phase 3 trial has enrolled 660 patients at 80-90 sites in 15 different countries. Ionis and Roche use lumbar punctures to inject an antisense oligonucleotide (ASO) into the cerebral-spinal fluid (CSF) in the spine, a procedure that repeats itself one or two times per month depending on which study participants are enrolled in (2). This study is especially promising due to Phase 2 evidence of reduction in mHTT in cerebrospinal fluid (CSF), which increases with higher medicine dosage (4). Phase 2 trials are trials in which drug efficacy is assessed in a smaller population (3).
In 2017, Wave Life Sciences announced the advent of the PRECISION-HD1 and 2 clinical trials (5). The current trial, PRECISION HD2, is characterized as 1b/2a, meaning the study tests the safety of the drug while also gathering suggestive data on its efficacy (5). Wave Life’s trial also does lumbar punctures but injects a different type of ASO into the CSF (5). This ASO, unlike the one that Roche developed, only targets the mutant huntingtin strand through single nucleotide polymorphisms (SNPs), or a unique nucleotide mutation in a person’s DNA (5). This means that the drug would only target the mutant huntingtin protein, which could be a better approach to huntingtin-lowering than eliminating the production of both the mutant and regular huntingtin protein (which is Roche’s current method) (5). However, Wave Life’s usage of SNP’s to eliminate the mutant protein means that Wave Life can only target about two thirds of the HD population with their drug because a certain subset of people with HD do not have the specific SNPs on the DNA that the pharmaceutical company is targeting (5). Wave Life Sciences is performing two clinical trials with two different ASOs to try to maximize the number of people that the drug could cure (5).
Voyager Therapeutics has developed an entirely different way of reducing mHTT that is called “AAV Gene Therapy” (6). AAV, short for Adeno Associated Virus, is a way in which Voyager can introduce their novel synthetic silencing RNA into target areas of the brain to “knockdown” or slow the production of the mutant Huntingtin protein (6). Though this drug, formally called VY-HTT01, is still waiting for approval from the FDA for a clinical trial, the results of preclinical studies seem promising (6). In mice, results show that VY-HTT01 reduced the levels of HTT messenger RNA significantly in the parts of the brain most affected by HD.
However, there are a couple of significant downsides to Voyager’s research (6). For one, Voyager needs to perform brain surgery to inject the treatment directly into the patient’s brain. Brain surgery requires surgeons to be extremely precise in the delivery of the treatment because if they make a mistake, the implications for patients are severe. Second, any side effects of this drug would last for a long time because the drug stays in the body for a patient’s lifetime (6). However, the good news about an AAV is that it may be a one-and-done treatment for HD (6). Assuming the drug works, HD patients for VY-HTT01 could improve symptomatically and not have to make frequent or long trips to a medical center to be administered a drug many times.
UniQure, like Voyager, has also created an AAV, but naturally there is some discrepancy. UniQure’s version of the AAV, called AMT-130, does not specifically target the mutant Huntingtin protein but instead targets both the non-mutant and mutant version of the protein (similar to Roche’s ASO) (7). However, even without selective targeting of the mHTT protein, AMT-130 shows promising reduction of mHTT in the deeper regions of the brain affected by HD in a preclinical trial with HD pigs (7). Another important result of uniQure’s pig study is that mHTT levels were also reduced in the cerebral cortex and “frontal areas of the brain” that HD affects in later stages of the disease, which implies that the drug can diffuse throughout the brain (7). This proof that AMT-130 can infiltrate different parts of the brain means the drug can have a more significant impact on the progression of the disease (7). The FDA recently approved uniQure’s Investigational New Drug (IND) application for AMT-130, enabling uniQure to prepare for a Phase I/II clinical trial to investigate the drug’s safety, tolerability, and function (7). The actual administration of the drug will begin at a number of locations in the US sometime before the end of 2019 (7).
PTC Therapeutics has developed an entirely different mechanism for drug delivery than any of the four pharmaceutical companies listed above: PTC’s new drug is a pill. The fact that the drug is a pill means that people would be able to take a simple pill that would improve their HD symptoms. PTC was able to do this through the creation of a “small-molecule” manufactured using their own novel pre-mRNA splicing techniques (8). Preclinical tests have promising results: the small molecule substantially reduces mHTT in cells, and in mice it reduces the mutant protein by as much as 80% (8). Currently, PTC is optimizing the drug to have the greatest effect on the brain while also evaluating drug dosage (8). Though PTC is still in the preclinical stage of drug testing, PTC announced that they may start clinical trials as early as the year 2020 (8).
Though these descriptions of current research are science-specific, this swath of recent advances in treating cognitive symptoms for HD has broader implications for HD and other diseases. One of these implications is that treatments in HD can act as a lead for other research. Many investigators decide to test similar treatments for different diseases because one idea worked for a certain disease. For instance, Voyager is performing two other studies that use the Adeno-Associated Virus vector but different micro RNA to target the genetic problems in ALS and Friederich’s ataxia (9). Another reason why these recent advances are so important is the hope that they give families and patients with HD and beyond. With increasing numbers of treatments, HD patients might have the chance to lead normal lives in the not too distant future. Moreover, with novel scientific advancements in HD research and their potential applications to other diseases, we, like the HD patients, look forward to a future with treatments for uncured diseases.
Edited by: Katrianna Urrea
Illustrated by: Lucy Chen