Huntington's Disease has been slow to give up its secrets. For a disease that is caused by 'just' a stutter in the genetic code for one protein, HD has certainly proved to be complex. It is a multi-hit disease, affecting numerous systems within the cells and no one knows which dysfunction occurs first although clues have been emerging.
Being proactive involves understanding how the research is done, from basic research to translational research to clinical trials, reviewing the results, and developing a strategy for fighting the disease.
Although the Lighthouse is calling for expedited clinical trials, we recognize that basic research into the structure and function of the protein and how it interacts with other proteins in the cells remains critical for the discovery and prioritization of therapeutic targets. The earlier a treatment can intervene in the disease process, the more effective it is likely to be.
The Research Pipeline
As the testing of compounds moves closer to human clinical trials, the pipeline narrows. Thousands of existing drugs, supplements, and compounds may be screened through specialized assays for properties that might identify agent that might act as treatments. Next, the small percentage of promising compounds might be tested in isolated cells containing the HD gene to see if these compounds delay cell death or rescue the cell. Researchers may also test them in simple animal models of neurodegeneration such as Drosophilia (fruitflies). Only a percentage will continue to show promise.
The "gold standard" for preclinical research is the HD mouse model. In 1996, Gillian Bates and colleagues developed the first transgenic mouse by inserting a long strand of human CAG repeats into the mouse. Although the gene for the huntingtin protein gene is an old one (even yeast have it), human beings are the only living creatures to get Huntington"s Disease. The HD mice are genetically manipulated to develop Huntington"s Disease so that more can be learned about the disease and potential treatments can be tested. There are now several models, each somewhat differently engineered, and each model mimics the human disease in somewhat different ways.
When a potential treatment delays onset, slows progression, and prolongs life in an HD mouse, researchers begin to get excited, especially if the potential treatment works in more than one model.
Before a compound can be prescribed for HD patients, it must go through three phases of clinical trials. In Phase I, a small number of volunteers are given the drug and closely monitored to see whether the drug is safe and well-tolerated.
Phase II involves more volunteers and focuses on finding the correct dose. Safety and tolerability continue to be monitored.
Phase III involves a still larger group – several hundred in HD research. Volunteers are randomly assigned to either the treatment group or a control group who receives a placebo. The study is double blinded - neither the subjects nor the researchers assessing them will know who received the compound and who received a placebo until the end of the study. Phase III takes much longer since enough time must pass for differences in disease progress to emerge between the treatment group and the control group, assuming the treatment is effective.
Unfortunately, the progression of a neurological disease like HD is difficult to measure since it is so gradual. It is expected that improvements caused by a treatment for HD will be difficult to measure as well. It's not like a cold, where the patient can quickly tell whether he or she is getting better. Right now the research community is actively looking for chemical changes in the blood and in MR (magnetic resonance) and PET (positron emission tomography) scans that may be an early indicator that the patient has stabilized or improved - long before the patient or doctor can determine it clinically. Such early indicators are called biomarkers, and when found can serve as surrogate (substitute) measures for disease progression. Surrogate measures will shorten the time needed for clinical trials.
If the results show that a compound is safe, well tolerated and effective, the FDA will be requested to approve the compound for clinical use. Because HD is a serious disease without a cure, the FDA will fast track its evaluation, taking about six months to review and make a decision.
The Future of Research
Here's what I think is going to happen:
- First, we will have cocktails of safe supplements and existing drugs that slow progression and buy time. We will be seeing more existing drugs and supplements tested over the next five years. Several compounds are in clinical trials with more in the pipeline. Researchers believe that a cocktail approach is the best one to pursue because HD is a multi-hit disease.
- Second, we will have drug development for more effective treatments. CHDI foundation is taking a leader in funding and facilitating this translational research. Experienced researchers from pharmaceutical firms know how to work with compounds to reduce toxicity and increase efficiency. We will probably see the first drug from CHDI in the next few years. Other researchers are also readying drugs for trials. In addition, since we don't know what private companies may be developing, there could be some surprises within this period as well.
- Third, we will eventually have virtual cures through gene silencing and restoration through stem cells. A lot of hard work is going to have to be done to get us there but the progress in mouse models has been remarkable.
Encouragingly, gene silencing and brain repair research does not just depend on funding for HD research but benefits from a much larger pool of funds. People with other dominant genetic disorders will benefit from the gene silencing research. Stroke patients as well as Alzheimer's, Parkinson's disease and other neurodegenerative disorders will benefit from the brain repair research. As success gets closer, we are seeing more and more funding go to these areas and more interest from pharmaceutical companies.
Finally, it's important to realize that all of the above research efforts are going on simultaneously right now. People often read about one potential treatment, then see a press release about a completely different one and assume that one strategy has failed and another is being tried. That is not the case. We know about a number of the major pathogenic processes in HD but we don't know which comes first or which are the most important so researchers are pursuing a number of targets and strategies. This is good; no one is wasting any time. If a drug or strategy is shown to be ineffective, then the resources will go to the other areas where researchers are achieving success.
The future has yet to be determined and we can affect it. We can urge our government to put more money into NIH research funding. We can lobby the research organizations and the FDA for expedited combination clinical trials. We need to stay on top of this until 'all of our ships are home safe in harbor' and no one is left behind.