Towards Treatment
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 exactly which dysfunction occurs first.
For many of us, being proactive in our personal fight against HD involves learning what we can about the research being done, from basic research to clinical trials, reviewing the results, and developing a personal strategy for fighting the disease.
Basic Research
Although my colleagues and I at the Lighthouse are calling for expedited, combination 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
The pipeline narrows as the testing of compounds moves closer to human clinical trials. Thousands of existing drugs, supplements, and compounds may be screened through specialized assays (laboratory analyses) for properties that might identify agents 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 (also called the R6-2 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 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 the HD mouse, researchers begin to get excited, especially if the potential treatment works in more than one model.
Clinical Trials
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 (a non-active compound, sometimes a sugar pill). 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 gradual and difficult to measure. It’s expected that an 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 things are getting better – long before the patient or doctor can determine improvement. 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 can 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. Creatine, CoQ10, ethyl-EPA are all in clinical trials; more drugs and supplements are ready to go.
Researchers believe that a cocktail approach is the best one to pursue because HD is a multi-hit disease. As far as the FDA is concerned we're not there yet because there are no treatments verified through Phase III clinical trials.
From the perspective of the HD community however, many people feel they can take action now. They've looked at evidence from the HD mouse models, from Phase I or Phase II clinical trials with HD patients, discussed possibilities with their doctors, and decided to take some safe supplements and possibly some existing drugs.
* Second, we will have drug development for more effective treatments. The High Q Foundation is taking the lead here in funding and facilitating this translational research through the Cure Huntington’s Disease Initiative (CHDI). 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 about five years. 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 techniques such as RNA interference (RNAi) and restoration through gene therapy or 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.
Advocacy
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.
Provided by Marsha L. Miller, Ph.D.
Answers to this question can be found through these links:
- CHDI
- This is the nonprofit drug development company which is making huge strides in getting us to significant treatments.
- The HD Lighthouse
- Published by Marsha and Steve and written by contributing editors. Research updates are provided on a timely basis.
- HDF Workshop Reports
- Published by the Hereditary Disease Foundation. These worshop reports are an excellent way to keep up with new developments in HD research.
