Drugs that increase the activity of PPAR-delta are added to the pipeline of potential treatments.
A serendipitous observation of low body temperature in Huntington disease mice has led to findings that may point to a possible treatment for Huntington disease in humans. Importantly, the possible treatment would involve drugs that have already been approved for use in humans for other conditions or that are in clinical trials.
Dr. Albert La Spada, director of the Center for Neurogenetics and Neurotherapeutics at the University of Washington Medical Center announced the findings in a plenary session at the 2008 American Society of Human Genetics annual meeting held November 11-15 in Philadelphia, Pennsylvania.
“My colleagues and I are very excited about the surprising results of our most recent research on Huntington disease because the findings could ultimately lead to a potential treatment for this currently fatal disease,” Dr. La Spada said. “Furthermore, our findings suggest that there are drugs already available and being used in human patients that could be possible new treatments.”
“We are very proud to have funded Dr. La Spada and his work," said Nancy Wexler, Ph.D., Higgins Professor of Neuropsychology, Columbia University and President, Hereditary Disease Foundation (HDF). "Dr. La Spada's work has been truly innovative and very promising. The HDF has a forty-year track record of supporting the best and brightest who are changing the cutting-edge of science. We often fund risky, creative research which then allows scientists like Dr. La Spada to get additional research support from agencies like the National Institutes of Health so that they can carry out their critical work.”
Dr. Wexler and the HDF played key roles in the work to locate and isolate the Huntington disease gene and to develop the genetic test for the disease. Her mother died of Huntington disease and Dr. Wexler is the subject of the recent biography, “Gene Hunter.”
Dr. La Spada was the recipient of the 2007 Lieberman Award from the HDF. The Lieberman Award is a special award given to select researchers to catalyze innovative proposals leading to the treatment and cure of Huntington's disease.
Huntington disease (HD) is an inherited fatal neurodegenerative disease that affects approximately 35,000 individuals in the United States. It generally has its onset in mid-adulthood and is relentlessly progressive with uncontrolled movements, cognitive decline, personality changes, and dementia. Death typically results from complications of the disease within 15-20 years of the onset of frank symptoms. There is presently no treatment for HD, although the first drug (tetrabenazine) to reduce the movement disorder symptoms of the disease was approved by the FDA in August. A famous victim of HD was Woody Guthrie, the American folksinger. Any child of an HD parent has a 50/50 chance of inheriting the disease.
HD is caused by mutations in a protein called huntingtin which is expressed in many different types of cells, including nerve cells. The normal huntingtin protein contains a stretch of the same amino acid and the number of amino acids in the stretch is increased in the mutated huntingtin protein found in HD patients. This causes the protein to take on an abnormal shape and form insoluble aggregates that are a characteristic pathological finding in the disease. The function of the normal huntingtin protein is unknown.
The stretch of a repeated amino acid in the huntingtin protein is coded for by a repeating sequence in the DNA, C-A-G, and thus HD is called a “triplet repeat” disease. Dr. La Spada was instrumental in identifying the first CAG triplet repeat disease (spinal and bulbar muscular atrophy) in 1991, while an MD/PhD student at the University of Pennsylvania. HD was identified as the second CAG triplet repeat disease in 1993. Since that time, a dozen or so other diseases have been found to be caused by triplet repeats in different genes.
Dr. La Spada’s work leading to the current discovery began five years ago at the University of Washington when he decided to investigate the possible therapeutic effects of cannabinoids (drugs containing an active ingredient of marijuana) in a mouse model of HD. In setting up his experiments, Dr. La Spada wanted to establish various baseline values and these included body temperature. Much to his surprise, he found that the HD mice (created by “transplanting” or inserting the human gene for mutant huntingtin into the mouse genome) developed significantly lower body temperatures than normal mice (by 3.5 – 10 degrees Celsius) as their disease became manifest. This surprising finding led him to investigate if the normal pathway of body temperature control in mice might be disrupted in HD mice. Interestingly, the decreased body temperature of HD mice had previously been overlooked despite their use in many studies.
In mice, body temperature is tightly controlled through metabolism carried out in a special form of fat called brown fat. To generate heat to maintain body temperature, a so-called futile cycle is activated in the brown fat cells. This cycle is called futile because two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat —heat that, in this case, serves to maintain the body temperature of the mouse. A particular protein (PPAR-gamma-coactivator 1-alpha, or more simply, PGC-1alpha) is key to activating this futile cycle.
Dr. La Spada hypothesized that the PGC-1alpha protein might be somehow inactivated in the HD mice as well as in HD patients. It was a particularly intriguing possibility because PGC-1alpha is also known to play a key role in turning on genes that lead to the production of more mitochondria, the energy powerhouses of the cell. Many studies over the years have shown that mitochondrial activity and energy production are adversely affected in HD patients.
To determine if PGC-1alpha function is truly affected in humans with HD, Dr. La Spada performed analyses to study the expression of genes that are normally turned on by PGC-1alpha in normal individuals. He found that, indeed, the expression of these genes is reduced in the brain cells of HD patients (presymptomatic or early symptomatic patients) who had died from other causes.
Dr. La Spada hypothesized that if you could increase PGC-1alpha function, it might be possible to ameliorate or eliminate the symptoms of HD. To test his hypothesis in mice, Dr. La Spada generated HD mice that had extra copies of the gene for PGC-1alpha, with the idea that production of more PGC-1alpha might overcome the problem seen in HD mice. Indeed this was the case. The HD mice with the extra PGC-1alpha genes exhibited dramatic improvements in characteristic HD symptoms of motor function deterioration, and the characteristic HD protein aggregates in neurons were also eliminated. These were “very exciting” findings, Dr. La Spada said.
Dr. La Spada next investigated the way in which PGC-1alpha activity might be reduced by mutant huntingtin protein. Although PGC-1alpha is not known to interact with huntingtin, a protein that interacts with PGC-1alpha was shown by Dr. La Spada’s group to bind to huntingtin. That protein is PPAR-delta, which, working together with PGC-1alpha, also plays a role in turning on genes that lead to the production of more mitochondria and thereby enhancing energy production.
Dr. La Spada performed experiments to determine if PPAR-delta function is disrupted in the brains of HD mice, and found that it was. This finding implicated PPAR-delta in the pathology of HD.
Dr. La Spada hypothesizes that mutant huntingtin protein might bind to PPAR-delta causing its inactivation. This in turn would disrupt PGC-1alpha function because it works in a complex with PPAR-delta.
If this is the case, it would offer a ready avenue toward the testing of a possible treatment for HD, because drugs known to increase the activity of PPAR-delta already exist. One is known as GW501516, an experimental drug from Glaxo-Wellcome (GlaxoSmithKline) that was the subject of a phase II trial completed in 2004. This trial was for indications other than HD.
The existence of such drugs is a tremendous asset because it means that if further studies in mice support the initial findings implicating PPAR-delta’s role in HD, then trials in humans could be greatly accelerated based on the results of clinical trial testing already done “Essentially, we have something we could take off the shelf, if you will, and give it to people, if the science supports it,” Dr. La Spada notes.
In addition to the possible energy defects that might be caused by inactivation of PGC-1alpha and PPAR-delta, an additional disease-related mechanism is possible, Dr. La Spada says. It is now known that retinoic acid participates in a cycle that leads to the preservation of cells and that this cycle is also co-activated by PPAR-delta. It is possible that the inactivation of PPAR-delta in HD may affect this cycle as well and thus favor cell death. This negative effect could be in addition to possible energy defects associated with inactivation of PPAR-delta’s function with PGC-1alpha.
Dr. La Spada is optimistic that the PGC-1alpha/PPAR-delta line of investigation will prove fruitful and lead to an effective intervention in the inexorable and deadly progress of HD.
“It’s one line of investigation, of a number that are going on, that are yielding some very promising leads for new treatments for HD. It’s not the only one, by any means, but it is certainly one of a number of advances that are being made. People are working very hard to develop these leads and to move to test them through cell culture studies and in animal models to determine whether any of these leads might be useful as treatments for patients with this disease. That’s the ultimate goal. The hope is that within the next few years, we’ll have a number of promising candidate drugs for testing in patients with HD.”
Dr. La Spada’s findings provide new light and hope for those who have traveled so long in the darkness and despair of this dread disease.
“I am very encouraged to hear Dr. La Spada’s results,” said Jonathan Monkemeyer, a 43-year-old engineer who recently testified to the FDA on behalf of approval of tetrabenazine and whose 46-year-old wife, Sheryl, suffers from HD. “I hope the science gets done quickly and saves a lot of lives.” Monkemeyer is presently creating a web site that he hopes will encourage more rapid communication among HD scientists and help “bridge the gap” between research and clinical benefits to patients. Monkemeyer and his family were recently the subjects of a story in the USA Today.