The attendees were welcomed by Louise Vetter who urged people to answer thequestionnaire from Project Aware which was available in the exhibition hall oncomputers and on paper. Without clinical trials, we will not have treatments andresearchers need to know why potential participants choose to participate or not.
A video about HD research was shown. Various researchers spoke: James Gusella, IraShoulson, Robert Pacifici, Don Lo, Marian DiFiglia, Michael Hayden, Marc Guttman,Neal Aronin, Chris Ross, Elena Cattaneo, and Leslie Thompson. HD was described as amodel genetic disease to research since understanding HD should also lead to insightsabout other neurodegenerative diseases. A number of researchers talked about theunusual degree of collaboration in HD, modeled by the Coalition for the Cure. Inaddition, patients and families are partners in the research. Treatments are coming but inthe words of Dr. Hayden, the effort is a “marathon and not a sprint.”
- Moderator Marcy McDonald talked about how far we’ve come in the last 25 years
- 1872 described
- 1967 CCHD/HDSA formed
- 1983 HD gene mapped
- 1993 HD gene identified
- 1996 First HD mouse models
- 1997 HDSA Coalition for the Cure
- 2001 PREDICT HD begins
- 2004 HDSA Coalition forms targeted teams
- 2004 HDSA partners with CHDI and HP
- 2005 COHORT begins
- 2005 REGISTRY begins
- 2008 TRACK HD begins
- 2008 Human iPS cells
- 2009 PREDICT HDv2 begins
- 2010 5 Year PHAROS HD completed
From 150 to 200 laboratories are now working on HD. Every researcher knows otherresearchers and they get each other involved.
Rick Morimoto spoke about Unlocking the Huntingtin Mysteries. Huntington’sDisease is caused by an expansion of the CAG repeat sequence. Aggregation is aninvariant consequence of CAG expansion, not just in HD but in other polyglutaminediseases as well. Aggregation is a sign that protein homeostatis has been disrupted.Proteins are essential constituents of the cells. They are the key subunits of molecularmachines of life. However, they are highly sensitive to their environment and readily goawry. They cell has chaperones and other defense mechanisms to protect againstmisfolded and damaged proteins but they become less efficient over time. Consequently,proteins are very much at risk during aging. A promising therapeutic strategy is to restore protein homeostasis.
Researchers have been able to restore protein homeostasis in model systems with avariety of methods. Proteins are ancient and similar across organisms. One animal thathas been useful for HD research is the nematode c. elegans. It has a three week lifespan.Using this model system, Dr. Morimoto has been able to identify genes that suppressaggregation.
Dr. Morimoto is part of the Coalition for the Cure team that is working on proteinhomeostasis . Other members are Gill Bates, Dave Borchelt, Ron Kopito, and ErichWanker. Over one million compounds have been screened. The goal is to find smallmolecules that will restore protein homeostasis and develop them into safe and effectivedrugs.
Steve Finkbeiner spoke about the Applications of Induced Pluripotent Stem Cells.Dr. Finkbeiner’s lab along with four others (Marcy MacDonald, Jim Gusella, LeslieThompson, and Clive Swenson) are part of the NINDS HD iPS Consortium.
Induced pluripotent stem cells are adult cells which have been preprogrammed to ‘turn back the clock’ to become stem cells again. One possible use for iPS cells is as replacements for missing cells. There are several obstacles to overcome first. The first is production; a large number of cells would be needed. The second is the need to insure survival. It may be that the cells would come under attack by the immune system. The third is safety. Stem cells can divide indefinitely so there is a possibility that they could produce tumors. The fourth is the difficulty of making sure that the cells become the right type of neuron. The fifth is getting the cells to talk to each other, to ‘wire’ correctly.
The second use of iPS cells is to improve the way drugs are screened as potentialtreatments. Because these are human cells with the disease, the effectiveness of assaysshould increase. The use of second generation robotic microscrope techniques allows forrapid testing of thousands and thousands of potential treatments in a short period of time.
The third use of the iPS cells is to help researchers better understand the mechanisms ofthe disease.
Dr. James Gusella spoke about genetic opportunities in observational studies. Observational studies are exactly that - observing what is going on without changing things or introducing anything. Examples include COHORT, PREDICT-HD, and TRACK-HD.
Individuals with HD vary in age of onset as well as the kind, severity, and order ofappearance of symptoms. If there is a symptom that changes at a particular rate withoutmuch individual variation, this would be a good measure for clinical trials.
Without observational trials, all we have is information from doctors, most of whom willnot see a large number of HD patients. We need more detail than they can provide.
Although the CAG count is negatively correlated with the age of onset, two individualswith the same CAG count can have an onset that is 40 years apart. Dr. Gusella and otherresearchers are looking for genetic modifiers that influence an earlier or later thanaverage age of onset. These genetic modifiers should be good clues to effectivetreatments. It should be possible to find them using DNA from observational studies butthousands of participants will be needed.
Mice can teach us a lot about biochemical effects of the HD mutation and they can beused as a first test of potential drugs. Because mice are mice, mice tend to teach us moreabout what’s important to mice as opposed to teaching us what’s important to people.Observational studies of people have advantages both for the patient and the researcher.
Advantages of doing observational studies to the patient:
- The course of their disorder can be followed over time by expert HD clinicians.
- They can contribute to improving the ability of the research community to designand carry out the most effective clinical trials to test potential treatments for HD
- The information gathered in the observation study can indicate that they have thecharacteristics needed for participation in a clinical trial to test new medicines for HD.
Advantages to the researcher:
- More efficient, more effective clinical trials.
- Clues to the fundamental mechanisms that operate during the course of HD =clues to new targets for treatment
- Clues to differences between individuals in the symptoms that develop, the timingwith which they occur and the rate with which they progress.
- Biological samples (DNA, cell lines and biological fluids) to investigate HD atthe molecular level.
- Because of rapid advances in the technical tools for performing genetic studies inhumans, it should be possible to find these genetic modifiers using informationand DNA from the HD observational studies.
- Since modifier genes alter the course of HD in human patients, they may providedirect clues to effective treatments.
The power of these studies is directly related to how many people participate in thestudies. Dr. Gusella urged the audience to participate in these studies.
Dr. Jane Paulsen spoke about PREDICTing Care – the Value of Pre-DiagnosticObservation. She thanked the many participants in the study. Another 80 participants are needed each year so there are still opportunities to join the study.
In addition to doing assessments of cognition and motor function and the MRIs, they are now working on measuring psychiatric problems.
In the nine years that the study has been operating, it has achieved the followingresults:
- Able to reduce the sample size for pre-HD clinical trials
- Identified markers 15 years prior to diagnosis.
- Developed a database of scans, bloods, DNA, phenotypic assessment
- Data is used to develop the models of disease.
- Facilitated the collaboration of clinical research teams, papers, presentations, new investigators, additional grants.
- Policy statement for disability legislations.
- Diagnostic consensus conference planning.
Your participation keeps the science moving forward.
Dr. Robert Pacifici spoke about Clinical Horizons: An Update on Therapeutic Directions. Dr. Pacifici is the Chief Scientific Officer for CHDI which is a very special biotech company. Their mission is to rapidly discover drugs that delay the onset or slow theprogression of Huntington’s disease.
CHDI is a not for profit biotech company. The bottom line is time, not money. It is foundation funded with about 80 million spent each year. It is exclusively dedicated to HD.
CHDI utilizes the virtual or outsourced model. They do not have their own labs. Allexperimentation is done via collaboration with other labs.CHDI’s goal is to ‘get the whole world to work on HD.’ To that end they have focusedon:
- Collaborative enablement – providing funding, reagents, an informationalwebsite, etc.
- Lowering the barriers for entry into HD research
- Leveraging integrated biotech firms
- CHDI driven targets
CHDI’s outreach to pharmaceutical companies has created new interest in HD.Pharmaceutical companies have thousands of compounds on the shelf which are notbeing used as drugs. CHDI will screen them while the company retains the rights tothem. Each compound may have ten to fifteen years of research going into it so ifsomething is promising for HD, they have a jumpstart.
Why is it taking so long to develop treatments? Instead of using old compounds, CHDIis working to develop new chemical entities for novel targets. Right now there are sixteen full speed ahead projects, five which have been discontinuedas ineffective, and more that are just getting started.
Several drugs are being optimized including an HDAC inhibitor and targets which targetKMO (kynurenine 3-monooxygenase) TG-2 (tissue transglutaminase), JNK3 (C-June Nterminalkinases), Sirt1, caspases, and PDHK (pyruvate dehydrogenase kinase).
Inhibiting Histone Deacetylase 4 (HDAC-4) is looking like a promising target. CrossingHD mice with mice missing HDAC-4 results in significant increase in survival time.
The most validated target is of course the HD protein itself. There are severalapproaches to this, RNAi, zinc finger proteins which target a DNA sequence, andantisense. In addition, they are also researching safe methods of delivery.
CHDI is working with Isis to develop antisense therapy for HD: The objective is toidentify an antisense oligonucleotide based therapeutic that reduces the levels ofhuntingtin in the brain. At this point there are some unknowns and uncertainties but it ispossible that if all goes well, clinical trials could start at the end of 2011.There are several drugs nearly the stage where an Investigation Drug Application (IND)will be filed. These include a CoQ10 analogue, an autophagy inducer, and a procognitivecompound.
Autophagy is a means of clearing the cell of damaged proteins. They are working withLink Medicine to research their compound LNK574. This compound, which upregulatesautophagy, was developed as a cancer treatment.