Science and Research

By Julie Stauffer

 Each year, the Science and Research Session at the Annual Conference of the Huntington Society of Canada provides an inspiring summary of the latest research into Huntington’s Disease and a glimpse of the work involved in finding a cure. This year they were fortunate to have two high-profile researchers on hand, both recipients of the Huntington Society’s NAVIGATOR awards. Dr Janice Braun discussed the work her laboratory is doing into chaperone molecules, while Dr Blair Leavitt summarised the exponential progress that has been made in understanding HD.

 Dr Janice Braun is an associate professor in the Department of Physiology and Biophysics and the faculty of Medicine at the University of Calgary and Dr Blair Leavitt is an assistant professor in the Department of Medical Genetics at the Department of Medicine at the University of British Columbia. He is also a scientist in the Centre for Molecular Medicine and Therapeutics and a consultant neurologist both at the UBC Neurogenetics Clinic and the HD Medical Clinic at UBC. In addition to being a NAVIGATOR program researcher, Dr Leavitt is also the first recipient of a research grant through the Laura’s Hope program

 Chaperones at the protein dance

For Dr Braun, chaperones aren’t parents or teachers keeping a watchful eye on teenagers at the high school prom. Instead they’re a large family of proteins that control the shape and location of other proteins within our cells.

 It’s an enormous job. Cells contain billions of proteins that turn over every two weeks or so: new ones are created and old ones are removed. It’s also an essential job. If a protein doesn’t fold into the correct shape or if it’s in the wrong part of the cell, it can’t perform its normal activity. This can lead to disease.

 That’s why it’s so intriguing that the so-called “protein balls” - formed from the protein produced by the Huntington gene - attract certain chaperones. Normally, chaperones are scattered throughout the cell. However, when the researchers in Dr Braun’s lab inserted the Huntington gene into a cell, they saw HSP 70 chaperones accumulate in the cell’s nucleus, concentrated around the protein balls. The researchers suspected this meant the chaperones were no longer doing their essential jobs throughout the cell.

 To test this suspicion, they measured the activity of another chaperone, cysteine string protein, which blocks calcium channels. When they inserted the Huntington gene into the cell, calcium started flowing through the channels.

 Clearly, expanded huntingtin - the protein produced by the gene for HD - was interfering with the work of the chaperones. And because calcium channels play an important role in sending signals between brain cells, these experiments give us new insight into how huntingtin disrupts brain cells.

 It also appears that huntingtin blocks the action of syntaxin, another calcium channel regulator. The more huntingtin protein researchers added, the less syntaxin was able to control the calcium channels and stop calcium from flowing into the cell.

 “This is particularly interesting given the problems with cellular calcium in nerve cells in Huntington disease,” says Dr Braun.

 Bridging the gap between bench and bedside

The last five years have been tremendously exciting, as our basic knowledge of HD has expanded exponentially. Much of the challenge now is to take all these things that scientists are discovering at the lab bench and transform them into treatments for people affected by HD.

While the major features of HD were well described by the late 1800s, the major breakthroughs began in 1983 when scientists first figured out which chromosome was home to the HD gene, and then ten years later when the CAG repeat expansion mutation in the HD gene was identified, direct genetic testing was identified, direct genetic testing became available, and the role of the CAG repeats in modifying disease onset were first understood.

 The next fundamental step forward in HD research happened in 1996, when the very first transgenic mouse model of Huntington disease was described. Once scientists had an animal model of the disease to study, research into Huntington’s exploded.

 The scientific progress made over the last five years has been so dramatic that it cannot be summarized in a few paragraphs: there have been literally thousands of papers describing different aspects of how the mutant huntingtin protein that is generated by the expanded CAG repeat in the HD gene affects cells.

 Dr Leavitt made a controversial prediction: he suggested that we may currently understand enough about the possible ways that mutant huntingtin protein causes HD to develop treatments - but we now need to translate this basic knowledge into effective clinical therapies. That means taking the most promising possibilities and cellular targets for treatments and testing these treatments, first in animal models and then in well designed human clinical trials.

 “We’ve learned a lot, but for everyone in the room, every day that goes by without a cure is one day too long,” he says. “So I’m not saying that we are already there - I’m saying we are almost there.”

 The development of accurate mouse models of HD is a key to developing treatments as quickly as possible. Dr Michael Hayden’s laboratory at The Centre for Molecular Medicine and Therapeutics has created transgenic mice that model many of the features of HD. In the early stages these mice are hyperactive, mimicking the increased movements seen in the early stages of Huntington disease. They also develop progressive problems with walking and balance, which are likewise symptoms in the human disease.

 When the mice reach six months of age, their brain cells start to show abnormalities and evidence for dysfunction, and by nine months of age, specific brain cells start to die. As the mice age, cognitive symptoms also begin to appear - the mice no longer learn as well as before.

 Because the mouse model reflects the human disease so well, it’s an excellent model for testing possible drugs, gene therapy, and cellular replacement therapy. Researchers in Dr Leavitt’s laboratory can measure the effects of a treatment on the physical and cognitive symptoms in the mice as they age, and they can also see whether or not the treatment prevents brain cells from dying.

 For example, Dr Leavitt’s lab has tested ethyl-EPA, a modified essential fatty acid (eicosapentaenoic acid or EPA) in the HD mice. They discovered that ethyl-EPA treatment of HD mice caused a modest improvement in some of the physical symptoms in the HD mice, but unfortunately didn’t seem to have any protective effects in the brains of these mice.

 In a recent human clinical trial of ethyl-EPA in HD the results were also mixed. A straightforward comparison of all the patients in the trial who received a placebo and patients who received EPA did not show a benefit as measured by a significant difference in neurological (motor) symptoms.

 However, a closer look at the data from the trial suggests that a sub-group of patients may have benefited from ethyl-EPA and one sub-group didn’t. This analysis raises the possibility that some patients who are earlier in the course of the disease or perhaps those with a lower CAG size may have a modest benefit. Unfortunately this trial was not designed to test this and only suggests a possibility that will require further trials to prove this. These new trials will start early in the New Year, and several Canadian centers will be involved.

 Does this mean people with HD should take fish oils? “My take-home message is that there is a lot of reasonably good evidence that increasing amounts of omega 3 fatty acids in your diet is probably safe for your heart and general health,” says Dr Leavitt. There’s also a possibility that it may be helpful for Huntington disease, he adds, “I don’t prescribe it to people, but I think it is probably not an unreasonable supplement to take.”

 There are other clinical studies going on at the moment. Researchers are waiting with great excitement to find out the results of a major European Riluzole study. Riluzole is an agent that may decrease excitotoxicity, one of the first things that go wrong in brain cells if you have HD. The HD brain cells may react too strongly to chemical signals from other brain cells, and as a result they become over-stimulated and eventually die.

 Riluzole has been proven to have some benefits in other neurodegenerative disease such as ALS.

A very large trial of 300 HD patients in Europe is almost completed now, and the results will be released very, very soon.

 “I don’t think that this is going to be a cure,” says Dr Leavitt, “but we’re hoping that it’s going to delay progression, which is what it did in ALS.” The minocycline study also wrapped up recently. A recent Huntington Study Group trial showed that minocycline - which is actually an antibiotic - is safe enough to use in wider trials designed to test how effective it could be at treating HD, although he made it clear that there is currently no evidence that minocycline is effective in HD patients.

 “We’re on the brink of new treatments,” Dr Leavitt concludes, but cautions that there are hurdles in making the transition from the lab bench to clinical trials and, ultimately, to successful treatments. The financial hurdle is obvious: research costs a lot of money. Finally, people and families affected by HD must be advocates for HD research with the various levels of government and with regulatory bodies such as the FDA and Health Canada. It is also critical that people become involved in clinical trials when they are launched. “Participate,” says Dr Leavitt. “In order to move forward, we need everyone involved.”

Acknowledgement:             Australian Huntington’s Disease Association (QLD) Inc – February 2005

Acknowledgement:             Horizon Huntington Society of Canada —2004 Annual Conference.

Reprinted:                            Gateway AHDA (NSW) Inc. January/February, 2005