HD Research - Past and Future
There has been an explosion of Huntington's Disease research since the gene was discovered in 1993. The discovery of the gene was the culmination of ten years of work by more than fifty collaborators in six labs and it represents a critical milestone in the effort to understand and treat the disease. As Dr. James Gusella, Coalition for the Cure researcher and member of the gene discovery team, has said, once the gene was found, the research could begin in earnest.
Huntington's Disease is caused by a genetic stutter in a gene that produces a large protein found in animals from yeast to humans. Its functions are not yet fully understood. There is a section of the gene that encodes for glutamine; the code consists of a series of the base pairs cytosine, adenine, and guanine (CAG repeats). In the Huntington's gene, these CAG triplets occur an abnormal number of times, changing the protein in ways that challenge the medium spiny neurons in the brain. Since the discovery of the HD gene, the genes for eight other polyglutamine disorders have been discovered.
Much has been learned about where and how the HD protein causes its damage. The most cell death occurs in the striatum but the cortex is affected too and cortical dysfunction has emerged as a major source of pathology.
The Huntington's Disease protein has been found to affect hundreds of cellular processes and components but several areas appear to be critical, including impaired protein folding and clearance, reduced cellular metabolism, neurotransmission problems, fragmentation of the protein and nuclear aggregation, and dysregulation of gene transcription with some genes being underexpressed and some overexpressed. Two of the affected genes which play a role in HD pathology include Brain Derived Neurotrophic Factor (BDNF) which is down-regulated and P53 which is up-regulated.
Much of what we now know about how Huntington's Disease develops has come about as a result of the development of the transgenic mouse in 1996 by Gillian Bates. Only humans get Huntington's naturally, but Dr. Bates was able to produce this model by inserting a short fragment of the human gene including about 150 CAG repeats.
Today there are various mouse models and each one captures a somewhat different set of Huntington's symptoms. The models include ones in which the entire human HD gene have been inserted (transgenic, full length) and ones in which extra mouse CAG repeats have been added to the mouse's own huntingtin's protein gene (knock-in models).
Various pathogenic processes have been found in the HD mice and other models and confirmed in human HD, adding to our knowledge about the disease. The mice are also used to test potential treatments.
Rigorous research has shown conclusively that the disease can be modified by various treatments in mouse models. This gives rise to the hope that at least some of these drugs, supplements, and interventions will make it through the research pipeline and become available treatments for people with the HD gene within the next few years.
The mouse models and new technologies have made it possible to identify targets for drugs, supplements, and other interventions that might prevent, slow or reverse disease progression. Knowing where to intervene allows researchers to find existing drugs that affect the target and test them as potential treatments. It is also the first step in drug development.
Translational research - a key part of the pipeline
Existing drugs could turn out to be effective but still be less satisfactory than we would like -- less bioavailable, less efficient, and with too many side effects. Pharmaceutical industry researchers know methods that can develop drugs further to make them better treatments. They have high throughput assays to screen existing compounds, and technologies to create new ones that might become safe, well-tolerated and highly effective treatments. Historically, the pharmaceutical industry's investment in Huntington's Disease research was limited because of the size of the market but this is changing now that basic research has identified a number of promising targets. Neurosearch, Prana Biotech, and Raptor Pharmaceuticals all have drugs in clinical trials while several other companies, including Lundbeck, Novartis, Isis and Vertex are working to develop new potential treatments.
The addition to the research community of CHDI, Inc., a nonprofit organization that pursues a variety of strategies to translate the knowledge gained through basic research into treatments for patients, has maximized our chances of having significant treatments soon. CHDI maintains biological and chemical repositories to facilitate academic research into Huntington's and provides resources to venture capital drive biotech firms to include HD in promising research and development efforts. CHDI lowers the barrier for the large pharmaceutical companies to go into HD drug development by testing their libraries of existing compounds for them. CHDI also contracts for services needed to advance their strategic plan such as fragment based screening for rational drug design and rigorous animal testing of drugs in the pipeline.
Various targets have been identified for the development of treatments, but the one with the most potential is the expression of the gene itself.
Just a dozen years ago, one researcher at an HDSA convention answered an audience member's question about gene therapy for Huntington's by saying that it would be wonderful but was still in the realm of science fiction. Today, there is the possibility that research with RNA interference and antisense drugs may bring about a virtual cure.
The first attempts at genetic intervention were aimed at recessive genetic disorders. Because these disorders require two copies of the disease gene to manifest themselves, the delivery of an additional, healthy gene should cure the disease, assuming it could be done efficiently and safely.
Huntington's Disease is a dominant disorder which means that only one copy of the gene is necessary for the disease to develop. The same approach might help somewhat by ensuring that more of the normal huntingtin's protein is made, but at best adding another normal gene could only be a modest treatment because the HD protein could continue to do its damage.
Then in 2002, scientists researching dominant genetic disorders took another look at RNA interference (RNAi). Although there is no known way to snip those extra CAG repeats out of the gene, intervention could take place at the messenger RNA level where the instructions to make the HD protein go out.
RNAi can be traced by to a serendipitous finding in plant science in 1990. A botanist was attempting to make a deeper purple petunia and inserted an extra couple of the gene encoding for purple coloration. Instead of achieving his goal, he found that the petunias were white. The reason remained a mystery until 1998 when researchers discovered that the addition of the gene activated a cellular defense mechanism. The cell reacts as if the new RNA is from a virus and launches an attack that silences both the new RNA and the original RNA, in this case silencing all of the color genes. It was quickly discovered that RNA interference also works in animal cells.
There are a number of critical issues to work out before a genetic intervention is available to HD patients. There is the problem of the expression of the normal huntingtin's gene. Recent research suggests that we continue to need the normal protein throughout our lives. Current RNAi technology partially shuts down both the normal and the HD gene. Research by Dr. Neal Aronin and Dr. Robert Friedlander has shown that it is possible to develop an allele-specific approach so that only the HD gene is silenced.
Another way to tackle this problem might be the development of an antisense approach with a drug which could be administered periodically. The goal would be to find an optimal time in which the cell can recover from the HD protein without being harmed by the absence of the normal protein. Isis Pharmaceuticals is working on this approach with funding from CHDI. Researchers from Dr. Michael Hayden's lab reported in 2010 that they were able to make an allele-specific antisense drug.
There are also issues of delivery and safety and toxicity. Currently, RNAi would be intrusive, involving entering the brain. It is possible that an antisense drug could be administered through a pump at the base of the spinal cord but that is less than ideal. Dr. Beverly Davidson is working on a method to introduce RNAi across the blood brain barrier by attaching it to a peptide derived from the rabies virus.
In addition, researchers must make certain that interventions at the RNA level affect the RNA target and nothing else. Despite the obstacles to be overcome, the potential of RNA-level interventions is so great that research will continue to be well-funded and involve many more researchers than those in the HD community.
Stem Cell treatments
Research with HD mice shows that once the production of the HD protein is halted, the mouse experiences much improvement. It is expected that the same will be true for Huntington's patients. However, it is likely that restorative treatments will be needed for patients in the later stages of the disease. Stem cell research is continuing around the world and a stem cell treatment may one day be available for HD patients.
The exciting possibility of being able to promote neurogenesis is raised by the work of Dr. Steven Goldman who was able to stimulate the growth of new neurons in the HD mice through adeno-viral vector delivery of genes for BDNF (brain derived neurotrophic factor) and for noggin, another trophic factor. In this approach, the patient's own reservoir of stem cells would be utilized to develop into neurons to replace those lost to the disease.
Dr. Jan Nolta and Dr. Vickie Wheelock are planning a clinical trial of mesenchymal stem cells which is expected to start in 2011. The meenchymal stem cells, which will be engineered to carry a neurotrophic factor, will be injected into the brain using tiny catheters. This is expected to be neuroprotective.
Although no one can be sure of what the future will bring, a likely scenario is that at least some of the clinical trials now in progress or being planned will result in a growing cocktail of treatments for HD patients, each one addressing a different pathogenic process. The genetic approaches have enormous potential but there are issues of delivery and safety to be worked out so, most likely, they will take longer to become available. However, many researchers beyond the HD community are pursuing genetic interventions into disease and we can expect to benefit from their work.
We can expect the unexpected. It has taken an enormous amount of work for researchers to learn about critical problems in HD and the disease has not given up all of its secrets yet. There may be significant targets for drug development yet to be discovered. As Dr. Robert Pacifici, Chief Scientific Officer for CHDI, has noted, "The ah ha moment may come out of left field." In addition, there may be drugs developed for other neurological diseases that will also be found to treat Huntington's Disease. And scientific research into areas far removed from Huntington's may hold promise for the future, just as RNAi emerged from the search for a more purple petunia.
For a disease with one known cause, an expansion of a polyglutamine tract within one gene which encodes for a protein, HD has certainly proved to be complex. As we learn more about how profoundly Huntington's Disease can affect the brain, we should be reminded of how resilient we are as human beings. The HD protein is made during development and from birth on in those who have inherited the gene and yet the brain is capable of dealing with the challenges presented for many years. This knowledge, coupled with the extraordinary progress made by scientists and HD families in the collaborative research process encourages us to believe that it will eventually be possible to hold the disease at bay through a combination of various treatments and interventions.
- Marsha L. Miller, Ph.D., 2011