Huntingtons Disease An Update on Latest Research HD Center of - PowerPoint PPT Presentation

Huntington’s Disease An Update on Latest Research HD Center of Excellence

HD Treatment g Current treatments are symptomatic. g Several compounds have delayed onset and slowed progression in mouse models. g Question remains to translate discoveries for human cures. HD Center of Excellence

Developing HD Treatments Cellular level Animal models Biomarker studies Clinical trials HD Center of Excellence

HD Center of Excellence Trafficking defects X RNAi X

The Development of RNAi http://www.macalester.edu/~montgomery/RNAi.html g When this system is activated, it causes an enzyme to chop up the RNA to find the relevant section of code. g It then binds that relevant section, containing the gene that we are trying to eliminate, and travels around the cell “looking” for other RNA that matches the code of that section. g When it finds the same code in other RNA it binds to these “target” RNA’s effectively blocking the production of harmful proteins. HD Center of Excellence

What does this mean? g It means, at the most simple level, that by “interfering” in the translation of certain genes into protein, RNAi may be able to offer a means to stop the progression of a disease in its tracks. HD Center of Excellence

Davidson and Henry L Paulsen (2004). Molecular Medicine for the brain: silencing of disease genes with RNA interference. The Lancet, Neurology Vol 3 pp145-149. g Targets the defective Huntington's gene, leaving the healthy version of the same gene to carry out its vital duties. g Mice who were given the RNAi treatment did not develop the symptoms seen in untreated mice. Nor did the treated mice show any signs of suffering from toxic side-effects, indicating that the technique is safe. The first clinical trials are likely to begin within the next five g years provided there are no signs that the technique is dangerous in humans. HD Center of Excellence

CLINICAL TRIALS TREND-HD 2CARE ATOMOXETINE CITALOPRAM CREST-E PREQUEL HD Center of Excellence

TREND-HD Participants consume 1g bid ethyl-EPA (i.e., g Miraxion) vs. placebo Unique protocol design allows all participants g exposure to ethyl-EPA (minimizing exposure to placebo) Hypothesis: May offer neuronal mitochondria g protection. May decrease chorea. HD Center of Excellence

2CARE g Participants consume 1200mg bid coenzyme Q10 (i.e., CoQ-10) g 60 month study design. Includes participants aged 16 and 17, as well adults. g Hypothesis: Participants taking CoQ-10 vs. placebo will prevent (or minimize) functional decline. CoQ-10 may prevent tissue degradation, improving neuronal health HD Center of Excellence

ATOMOXETINE g Participants consume 40mg bid atomoxetine vs. placebo g Unique protocol design, allowing all participants exposure to atomoxetine (i.e., crossover design) g Hypothesis: Participants taking atomoxetine vs. placebo will demonstrate an improvement in executive functions and motor functions. Participants taking atomoxetine vs. placebo will also experience a decrease in psychiatric impairment. HD Center of Excellence

CITALOPRAM g Participants consume 20mg qd citalopram vs. placebo g Unique study design: Two week single-blind placebo run-in g Hypothesis: Participants taking citalopram vs. placebo will experience an increase in their executive function capabilities and a decrease in psychiatric impairment. Interestingly, improvement in motor symptoms is not expected. HD Center of Excellence

CREST-E g Participants consume 30g qd Creatine vs. placebo for 36 months g Simple study design. Parallel groups, 1:1 ratio. g Hypothesis: Participants taking Creatine vs. placebo will maintain (or increase) their total functional capacity from baseline. HD Center of Excellence

PREQUEL g Presymptomatic participants consume 1200mg qd or 2400mg qd coenzyme Q10 vs. placebo g Unique protocol design: Participants are presymptomatic. Participants are enrolled for 18 months. g Objective: To establish treatment tolerability aspects (i.e., 1200mg vs. 2400mg) in presymptomatic participants. To assess the feasibility of implementing a preventative therapeutic trial. HD Center of Excellence

Research to Detect HD As Soon As Possible g Movement-Motor measures g Thinking measures g Mood measures g Brain measures g Potential blood measures? g Potential genetic markers? HD Center of Excellence

Measures for clinical trials in HD NP Test Low Cost and Time MRI Computerized fMRI High Cost Paper and Pencil Cognitive and Time PET Imaging Assessment Assessment HD Center of Excellence

Clinical Trials: Model of Intervention in HD 90 Neurobiological marker Neurobiological marker 90 80 80 70 70 60 60 50 50 Diagnostic (Motor) Threshold Diagnostic (Motor) Threshold 40 40 30 30 20 20 10 10 0 0 20 25 30 35 40 45 50 55 20 25 30 35 40 45 50 55 Age Age CAG ≥ 39 Untreated CAG ≥ 39 Untreated CAG ≥ 39 Treated at diagnosis CAG ≥ 39 Treated presymptomatically HD Center of Excellence

Possible Biomarkers: Cross-Sectional Data from Predict Self-Tim ed Finger Tapping W ord List Learning Tapping Consistency(1/SD, in msec -1 ) 30 0.030 Total Correct (out of 36) 28 0.025 26 0.020 24 0.015 -35 -30 -25 -20 -15 -10 -5 -35 -30 -25 -20 -15 -10 -5 Estim ated Years From Diagnosis Estim ated Years From Diagnosis M otor Exam Score Striatal Volum e 12 18 10 17 Total Severity Score 16 cubic cm 8 15 6 14 4 13 2 12 -35 -30 -25 -20 -15 -10 -5 -35 -30 -25 -20 -15 -10 -5 Estim ated Years From Diagnosis Estim ated Years From Diagnosis HD Center of Excellence

Striatum (caudate & putamen): the brain region most affected in HD Unaffected Patient with HD Caudate Putamen HD Center of Excellence

Uses of Markers in Clinical Trials g Closer to clinical diagnosis? g Near transition to period of more rapid decline? Paulsen et al. Predict baseline curves paper, in review (2007) Speeded Finger Tapping Motor Exam Score Striatal Volume 0.0036 0.0038 0.0040 0.0042 0.0044 0.0046 0.0048 0.0050 0.0052 12 18 Tapping Rate (taps/msec) 10 17 Total Severity Score cubic cm 16 8 15 6 14 4 13 2 12 HD Center of Excellence -35 -30 -25 -20 -15 -10 -5 -35 -30 -25 -20 -15 -10 -5 -35 -30 -25 -20 -15 -10 -5 Estimated Years From Diagnosis Estimated Years From Diagnosis Estimated Years From Diagnosis

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Acknowledgments Study Investigators Henry Paulson, M.D., PhD Bev Davidson, M.D., PhD Leigh Beglinger, PhD Research Assistants Elizabeth Penziner, M.A., M.P.H. William Adams, B.A. Stacie Vik, B.A. Special thanks to the faculty and staff of the Paulsen Neuropsychology Lab at The University of Iowa Carver College of Medicine HD Center of Excellence