Huntington's disease (HD) is an inherited autosomal dominant disorder of the central nervous system. The disease is passed from parent to progeny with a 50 percent chance of inheritance. HD is a polyglutamine disorder. Normal individuals have 7 to 34 CAG repeats in the Huntingtin (Htt) gene which encode glutamine amino acids in the Htt protein. The CAG repeats are expanded and unstable in HD patients, with repeat lengths inversely correlating with age of disease onset. Repeat lengths greater than 40 glutamines invariably cause HD, and repeats of greater than 100 glutamines typically cause juvenile onset. HD is a neurodegenerative disease characterized by movement disorder, dementia, and psychiatric disturbance which typically develops in the fourth or fifth decade of life with a disease duration of 10 to 30 years. Thirty thousand Americans have HD at an annual cost to American society of $2.5 billion with another 250,000 individuals at risk to inherit the disease. There is no cure or preventative for HD. Theories of HD pathogenesis include excitotoxicity, inappropriate apoptosis, mitochondrial dysfunction, and transcriptional dysregulation. Present treatment of HD is management of symptoms with currently marketed therapeutics. There is great interest in the development of an effective therapeutic for HD. Numerous published investigations have shown effectiveness in preclinical studies of a significant number of compounds but few if any results have translated to efficacy in humans. Human HD therapeutics based on the underlying pathogenic mechanisms of HD have great promise in preventing or stopping progression of the disease. There are indications in model systems as well as in humans that enzymatic processing or cleavage of Htt is a prerequisite for HD. One key mechanistic intervention point appears to be the cleavage of Htt by caspase 6 at amino acid 586. Studies have shown that preventing caspase 6 cleavage at Htt586 by changing the amino acids of the caspase 6 recognition site prevents development of the HD like neuropathogenesis in a HD mouse model system. Therefore, development of a caspase 6 enzymatic activity inhibitor would seem to be a advantageous therapeutic goal. However, caspase 6 processes many other important biological substrates and therefore such an inhibitor would predict significant side effects. With an innovative approach, we propose to identify and develop molecules that bind at or near Htt586 to prevent caspase 6 from binding and cleaving specifically at the Htt586 site. We call such a compound a substrate binding inhibitor molecule (SBIM). Because the amino acid sequence around the caspase 6 Htt586 cleavage site is different from other caspase 6 substrate sites, such a SBIM would be specific to the Htt586 and specific to HD. The identification of a Htt586 SBIM will validate the SBIM strategy, set the stage for development of an HD therapeutic in Phase II research and provide a potentially promising route to the development of an effective HD therapeutic.
Public Health Relevance: Thirty thousand Americans currently have Huntington's disease (HD) at a cost to American society of over $2.5 billion per year. Huntington's disease (HD) is an inherited autosomal dominant neurodegenerate disorder that is caused by increased repeats of CAG in the Huntingtin gene. HD symptoms, characterized by movement disorder, dementia, and psychiatric disturbance, typically begin developing in the third and fourth decade of life, with a disease duration of 10 to 30 years. Currently there is no cure or treatment for HD. We are identifying a substrate binding inhibitor molecule, an innovative approach to the development of a HD therapeutic.
Public Health Relevance: Project Narrative Thirty thousand Americans currently have Huntington's disease (HD) at a cost to American society of over $2.5 billion per year. Huntington's disease (HD) is an inherited autosomal dominant neurodegenerate disorder that is caused by increased repeats of CAG in the Huntingtin gene. HD symptoms, characterized by movement disorder, dementia, and psychiatric disturbance, typically begin developing in the third and fourth decade of life, with a disease duration of 10 to 30 years. Currently there is no cure or treatment for HD. We are identifying a substrate binding inhibitor molecule, an innovative approach to the development of a HD therapeutic.
Project Terms: Absorption; Active Sites; Adolescent; Adolescent Youth; Adverse effects; Affect; Affinity; Age; Agonist; Amentia; American; Amino Acid Sequence; Amino Acids; Animal Model; Animal Models and Related Studies; Animal Testing; Apopain; Apoptosis; Apoptosis Pathway; Apoptotic Cysteine Protease MCH2; Apoptotic Protease Mch-2; Arginine; Arginine, L-Isomer; Assay; Bears; Binding; Binding (Molecular Function); Binding Proteins; Bioassay; Biochemical; Biologic Assays; Biological; Biological Assay; Biological Function; Biological Models; Biological Process; Body Tissues; CAG repeat; CASP-3; CASP3; CASP6 Protein; CASPASE 6, Apoptosis-Related Cysteine Protease; CNS Diseases; CNS disorder; CPP-32; CPP32; CPP32 protein; CPP32B; CPP32beta; Caspase 3, Apoptosis-Related Cysteine Protease; Cations; Cell Death, Programmed; Central Nervous System Diseases; Central Nervous System Disorders; Chemicals; Cleaved cell; Clinical Trials, Phase I; Common Rat Strains; Complex; Computer Simulation; Computerized Models; Cysteine Protease CPP32; DNA Sequencing Facility; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia; Development; Disease; Disease Progression; Disorder; Drug Delivery; Drug Delivery Systems; Drug Design; Drug Exposure; Drug Kinetics; Drug Targeting; Drug Targetings; Drug toxicity; Drugs; Dyskinesia Syndromes; Early-Stage Clinical Trials; Effectiveness; Enzyme Antagonist; Enzyme Inhibitor; Enzyme Inhibitor Agent; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Esteroproteases; Evaluation; Excretory function; Flies; Funding; Genes; Gln; Glutamine; Goals; Guidelines; HD protein, human; Hereditary; Hot Spot; Hot Spots (Area of Increased Mortality); Human; Human, General; Huntingtin; Huntingtin Protein; Huntingtin protein, human; Huntington Chorea; Huntington Disease; Huntington disease protein, human; Huntington's; Huntington's Disease; Huntington's Disease Pathway; Huntington's disease gene product; Huntingtons Disease; Hydrogen Bonding; Hydrolysis; Hydrophobic Interactions; IT15 protein, human; In Vitro; Incidence; Individual; Inherited; Intermediary Metabolism; Intervention; Intervention Strategies; Investigation; Kinetic; Kinetics; L-Arginine; L-Glutamine; L-Tryptophan; L-Tyrosine; Laboratories; Lead; Learning; Length; Levotryptophan; Libraries; Life; Ligand Binding Protein; Ligands; METBL; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Maps; Marketing; Mathematical Model Simulation; Mathematical Models and Simulations; Medication; Metabolic Processes; Metabolism; Methods; Mice; Moab, Clinical Treatment; Model System; Modeling; Models, Biologic; Models, Computer; Modification; Molecular Interaction; Monoclonal Antibodies; Movement Disorder Syndromes; Movement Disorders; Murine; Mus; Mutate; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neuropathogenesis; Nuclear Magnetic Resonance; Onset of illness; Organ; PARP Cleavage Protease; Parents; Pathogenesis; Pathology; Patients; Pb element; Peptidases; Peptide Hydrolases; Peptide Library; Peptides; Peptoids; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Physiologic; Physiological; Poly Q; Process; Process of absorption; Progressive Chorea, Hereditary, Chronic (Huntington); Proteases; Protein Binding; Protein Fragment; Protein Structure, Primary; Proteinases; Proteins; Proteolytic Clipping; Proteolytic Enzymes; Proteolytic Processing; Publishing; Q. Levoglutamide; Radiation, X-Rays; Radiation, X-Rays, Gamma-Rays; Rat; Rattus; Receptor Protein; Reproduction; Research; Risk; Roentgen Rays; Role; Route; SBIR; SBIRS (R43/44); SCA-1; SREBP Cleavage Activity 1; Scheme; Sequencing Core; Shapes; Simulation, Computer based; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Societies; Sodium Chloride; Sodium chloride (NaCl); Specificity; Staging; Structure; Surface; Symptoms; System; System, LOINC Axis 4; TYR; Testing; Therapeutic; Tissues; Toxic effect; Toxicities; Transgenic Animals; Translating; Translatings; Treatment Side Effects; Trinucleotide Repeats; Triplet Repeats; Tryptophan; Tyrosine; Tyrosine, L-isomer; United States; Universities; Ursidae; Ursidae Family; Washington; X-Radiation; X-Rays; Xrays; Yama; Yama protein; aminoacid; analog; base; caspase-3; caspase-6; cleaved; codon reiteration; combinatorial; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; cost; cysteine protease P32; design; designing; disease duration; disease length; disease onset; disease/disorder; disorder onset; dosage; drug development; drug/agent; enzyme substrate; excitotoxicity; excretion; fly; gene product; good laboratory practice; heavy metal Pb; heavy metal lead; human Huntingtin protein; human tissue; illness length; in silico; in vitro Assay; in vivo; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; interest; interventional strategy; juvenile; juvenile human; language translation; mitochondrial dysfunction; model organism; mouse model; neurodegenerative illness; novel therapeutic intervention; para-Tyrosine; pharmacophore; phase 1 study; phase 1 trial; phase I trial; poly(glutamine); polyQ; polyglutamine; preclinical study; prevent; preventing; professor; protein sequence; protocol, phase I; public health relevance; receptor; salt; side effect; small molecule; social role; symptom management; theories; therapeutic target; therapy adverse effect; tissue culture; treatment adverse effect; virtual simulation
