TargetsTargets and and Mechanisms Mechanisms Validated Validated TrialsTrials on on the the Horizon Horizon Research Investors Report 2011 TABLE OF CONTENTS Huntington’s Disease Research in 2011: Targets and Mechanisms Validated; Trials on the Horizon FINDING AND VALIDATING TARGETS 4 DRP1 4 Ku705 5 A CLOSER LOOK AT THE HD PROTEIN 6 HR Protein aggregates visualized 6 Form of the HD protein associated with neurodegeneration identified 7 DISCOVERING/DEVELOPING NEW DRUGS AND UNDERSTANDING THEIR MECHANISMS 10 Dantrolene appears to be neuroprotective 10 Melatonin delays onset and prolongs survival in the R6/2 Mouse 11 KMO Inhibitor developed 12 New Caspase Inhibitors identified and Optimized 14 Quinazoline derivative looks promising 15 Phosphodiesterase-10 inhibitors 16 Novel benzoxazine compounds may be neuroprotective 18 Dimethylfumarate is helpful to the YAC128 Mouse 18 IPSC Consortium creates stem cell lines 19 FINDING AND VALIDATING BIOMARKERS 21 H2AFY 21 Protein Aggregates 22 TRACK-HD 22 UNDERSTANDING THE DISEASE COURSE AND IMPROVING CLINICAL MEASURES 25 Progression of HD and MRI imaging 25 Enroll-HD 25 POTENTIAL TREATMENTS MOVING CLOSE TO CLINICAL TRIALS 27 RNAi Primate Study 27 ASOs can be made allele specific 27 Mesenchymal stem cells with BDNF 28 CLINICAL TRIALS 30 Lessons from Dimebon 30 Neurosearch -- Huntexil (ACR-16) 31 Prana Biotech Copper Chelator 31 Siena Biotech Sirt1 Inhibitor 32 THE OTHER MEMBERS OF THE RESEARCH TEAM - THE PARTICIPANTS 33 FINAL THOUGHTS 35 HD DRUG DEVELOPMENT PIPELINE CHART 36 HDSA COALITION FOR THE CURE 37 HDSA CENTERS OF EXCELLENCE 38 Cover Photo: Polarizing optical microscopy image of huntingtin peptide aggregates stained with Congo Red. Courtesy of Dr. Christopher Stanley, Neutron Scattering Science Division, Oak Ridge National Laboratory. Targets and Mechanisms Validated: Trials on the Horizon 2 Research Investors Report 2011 RESEARCH INVESTORS’ REPORT 2011 Targets and Mechanisms Validated: Clinical Trials on the Horizon he year 2011 was a very fertile one for Huntington’s disease research. The exciting prospect Tof gene silencing worked its way through to testing in primates; we were able to actually see protein aggregation at its earliest and most toxic stages; many new potential therapeutic target pathways were identified; several biomarker candidates that will allow the measurement of effectiveness of future therapeutics were brought close to validation; and a number of new drugs were added to the HD pipeline of potential treatments based on research which focused on both effectiveness and the mechanism of action. New developments were announced almost weekly. Some of the major findings included in this report were published less than two weeks before it was completed. Last year we reported on a growing pipeline of potential treatments that either target the expression of the gene or one of a variety of pathogenic processes. Researchers whom HDSA has been funding for many years have been key to the effort to move treatments from the lab to the clinic through their leadership in discovering targets, developing drugs, and providing support for translational efforts that led to clinical trials. As an illustration of how critical your donations to HDSA research has been to the progress we’re seeing today, we’ve color-coded (in blue) names of members of the HDSA Coalition for the Cure, and other scientists who have received Grants or Fellowships from HDSA as well. As the pipeline has grown, it has become increasingly clear that we need to maximize the probability that clinical trials will be successful. Giving priority to those drugs with a validated target and a known mechanism, finding biomarkers, and improving clinical measures are ways to accomplish this goal. This year we have seen major progress in research directed to these areas with scientists doing careful work to find and validate targets, develop drugs which address those targets, and understand the mechanism involved in potential treatments. There are new drugs in development and new clinical trials on the horizon. HDSA continues to focus on the need to educate people about potential treatments and the importance of observational and clinical trials so that members of the community can make informed decisions about how to participate in efforts to evaluate potential therapies for FDA approval. Targets and Mechanisms Validated: Trials on the Horizon 3 Research Investors Report 2011 Finding and Validating Targets Researchers are using multiple research methods and models of Huntington’s disease to find and validate targets. DRP1 is Identified as a Promising Therapeutic Target Impaired energy metabolism has been identified as a major pathology in Huntington’s disease. As work by Dr. Marcy MacDonald, Massachusetts General Hospital and Harvard Medical School, has shown, mitochondria, the cell’s energy factories, are not intrinsically defective but are thought to be mismanaged in some way in HD. A University of Central Florida research team lead by Dr. Ella Bossy-Wetzel has discovered how this occurs. The HD protein interacts abnormally with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1). DRP1 is the protein that is responsible for mitochondria fission in the fission-fusion cycle1. DRP1 becomes overactive and upsets the balance in the cycle. The mitochondria fragment, mitochondrial transport becomes impaired, and cells die. The researchers used multiple models and techniques to understand and confirm the role of DRP1. They first examined rat cortical cells. Those with a normal polyglutamine region had healthy mitochondria whereas those with expanded polyglutamine stretches (expanded CAG repeats) had fragmented mitochondria. Those with 97 CAG repeats had more fragmentation than those with 46 CAG repeats. Time lapse imaging showed an increase of fission events compared to fusion events. Fragmentation was correlated with cell death. Dr. Bossy-Wetzel and colleague examines rat cortical cells Human skin cells were next examined. Fragmentation was also found in cells from people with Huntington’s disease, more so in those with juvenile rather than adult onset. In addition, the researchers also examined mitochondrial transport and velocity in rat cortical cells. Transport and velocity were normal when the CAG repeats were normal but decreased with expanded repeats. Again, the impairment was more severe with higher repeats. This is important because decreased transport would likely have a negative effect on energy distribution especially at synapses where demand for energy is high. The researchers confirmed their findings in the YAC1282 mice, finding an increase in mitochondrial fragmentation before the onset of symptoms, neurological deficits, aggregate formation, and cell death. 1. Fission-Fusion Cycle -- In recent years it has been discovered that individual mitochondria do not exist as permanently distinct entities as was previously believed but instead form a dynamic network within which proteins, lipids and mitochondrial DNA are exchanged by rapid divisions and fusions. The reason for this is not clear but it has been speculated that this is a method which evolved to combat the accumulation of mitochondrial DNA mutations. Targets and Mechanisms Validated: Trials on the Horizon 4 Research Investors Report 2011 The researchers next examined the possible role of DRP1 in fragmentation. Examining both the YAC128 mice and human brain tissue, they found that while the normal huntingtin protein only weakly interacts with DRP1 at best, the HD protein binds to DRP1 and increases its enzymatic activity. Finally, they found that restoring the normal fission-fusion cycle by replacing DRP1 with a mutant version (DRP1 K38A) which promotes fusion, they were able to rescue the cell from mitochondrial fragmentation, mitochondrial transport impairment, and cell death. More work is planned to explore whether this finding can be translated into a treatment. Ku70: a regulatory factor for DNArepair proposed as a therapeutic target A team of Japanese scientists and Dr. Erich Wanker, Max Delbruck Center for Molecular Medicine, Berlin, Germany, have identified Ku70 as a new therapeutic target in Huntington’s disease. Ku70 is a critical protein involved in DNA double strand break (DSB) repair. In previous research, they found that the HD protein directly interacts with and impairs Ku70 and that restoring Ku70 increases the survival time of the R6/2 mice. Dr. Erich Wanker Working with several different drosophila models of HD in this study, they found that Ku70 co-expression reverses shortened lifespan, impaired motor activity and eye degeneration. In contrast, Ku70 reduction makes these HD caused pathologies more severe. The authors conclude that their research provides a rationale for targeting Ku70. They plan to proceed with translational efforts, either using viral vectors to express Ku70 or developing a drug that would mimic Ku70’s affect on double strand DNA breaks. 2. YAC128 Mouse – a mouse model of Huntington’s disease that expresses the full-length human HD gene with 128 CAG repeats. The model closely replicates the slow progression of behavioral deficits and striatal neuronal loss characteristic of the human disease. Targets and Mechanisms Validated: Trials on the Horizon 5 Research Investors Report 2011 A Closer Look at the HD Protein The Huntington’s disease protein is a major target because it causes the disease, but it is not fully understood. This year, researchers have made some major advances in understanding the nature