Huntington's disease (HD) is an autosomal dominant, progressive and fatal neurodegenerative disease that effects 200,000 people worldwide. Despite discovery of the gene more than 25 years ago and more than 150 clinical trials, there is still no effective treatment for HD. The development of any therapy that slows, halts, or prevents disease would have a major impact on the patients and their families. HD is caused by the expansion of a CAG repeat in the huntingtin gene (HTT), resulting in an expanded stretch of glutamines in the huntingtin protein. Normal huntingtin protein (HTT) is essential throughout the body and brain to regulate cell physiology including synaptic transmission and neuroprotection, cell division and differentiation, gene transcription and the DNA damage response. In patients with HD, the expanded polyglutamine tract causes mutant HTT (mHTT) to fold abnormally, resulting in aberrant post-translational modifications and cleavage to generate toxic mHTT fragments. The N-terminal mHTT fragments form oligomers that interact with many cellular proteins, disrupting cell function, resulting in increased levels of mHTT and causing mHTT inclusions. Substantial neuronal dysfunction and death occur in striatal medium spiny neurons (MSNs) and the cerebral cortex. Experimental procedures that lower mHTT have reversed disease symptoms in animal models of HD. However, clinical translation of this mechanism of action has stalled and is, in part, hypothesized to be due to nonselective lowering of both the essential HTT as well as mHTT. In addition, some of the drug candidates in clinical trials target the brain exclusively, use therapeutic modalities that require invasive delivery systems and leave the rest of the body untreated. Therefore, an orally delivered, systemically distributed, brain-penetrant therapeutic that selectively eliminates toxic mHTT while sparing the functional forms of HTT to support normal physiology could offer an effective treatment for all HD patients. By applying its expertise in screening, Origami Therapeutics (OT) has identified a chemical scaffold, represented by OR1-113, that prevents mHTT aggregation, and selectively lowers mHTT levels in cell-based assays by enhancing degradation through an autophagy pathway as demonstrated in HD patient-derived fibroblasts, human HD iPSC-derived medium spiny neurons and in vivo in the cortex and striatum of the YAC128 mouse model of HD. Twelve analogues of ORI-113 have been designed. The efficacy and drug-like properties of OR1-113 and 12 analogues will be compared in HD patient iPSC-derived MSNs and in vitro absorption, distribution, metabolism, and excretion studies will provide insight regarding the metabolism and potential interactions of the drug compounds (Aim 1). Pharmacokinetic (PK) and brain exposure profiles of four lead compounds selected from Aim 1 will be determined in mice for oral availability (Aim 2). The top two ranked leads will be evaluated in a combined PK/Pharmacodynamic and safety study in YAC128 mice with oral administration (Aim 3). These studies will identify a lead therapeutic drug candidate that will move into Investigational New Drug Application studies that are required prior to initiation of clinical testing.
Public Health Relevance Statement: NARRATIVE Huntington's disease (HD) is an inherited, debilitating, and fatal neurodegenerative disease for which there is no effective treatment. HD is caused by a mutation in the huntingtin gene, which is essential for normal body and brain function, however, in patients with HD, the huntingtin protein is susceptible to misfolding that results in nerve cell dysfunction and cell death. Origami Therapeutics, Inc. has developed and will test and then select an orally available drug that lowers the levels of the toxic misfolded huntingtin protein, eliminating the cause of HD as a potential treatment to prevent HD progression, morbidity, and mortality.
Project Terms: absorption; Oral Drug Administration; intraoral drug delivery; Oral Administration; Autophagocytosis; autophagy; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Blood; Blood Reticuloendothelial System; Brain; Brain Nervous System; Encephalon; Cell Death; necrocytosis; Cell Differentiation process; Cell Differentiation; Cell division; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Cerebral cortex; Cerebrospinal Fluid; cerebral spinal fluid; spinal fluid; Clinical Trials; Corpus striatum structure; Corpus Striatum; Striate Body; Striatum; striatal; Cystic Fibrosis; Mucoviscidosis; Disease; Disorder; DNA Damage; DNA Injury; Drug Compounding; Drug Preparation; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Family; Fibroblasts; Genes; Glutamine; Gln; L-Glutamine; Q Levoglutamide; Q. Levoglutamide; Grant; Heart Diseases; Cardiac Diseases; Cardiac Disorders; heart disorder; Blood Tests; Hematologic Tests; Hematological Tests; Hematology Testing; Human; Modern Man; Huntington Disease; Huntington Chorea; Huntington's; Huntington's Disease; Huntingtons Disease; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Metabolism; Intermediary Metabolism; Metabolic Processes; Liver Microsomes; Mitochondria; mitochondrial; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Persons; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Synaptic Transmission; Neural Transmission; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Physiology; Plasma Proteins; Aspiration Pneumonia; Post-Translational Protein Processing; Post-Translational Modification Protein/Amino Acid Biochemistry; Post-Translational Modifications; Post-Translational Protein Modification; Posttranslational Modifications; Posttranslational Protein Processing; Protein Modification; Proteins; Rest; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Solubility; Mass Spectrum Analysis; Mass Photometry/Spectrum Analysis; Mass Spectrometry; Mass Spectroscopy; Mass Spectrum; Mass Spectrum Analyses; Testing; Time; Tissues; Body Tissues; Genetic Transcription; Gene Transcription; RNA Expression; Transcription; Measures; Neurites; falls; Investigational New Drug Application; Organ; Procedures; Peripheral; Area; Clinical; Penetration; Phase; Medical; Chemicals; Susceptibility; Predisposition; excretion; Excretory function; insight; Individual; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Disease Progression; Voluntary Muscle; Skeletal Muscle; analog; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; Genetic; Atrophic; Atrophy; scaffold; scaffolding; Intravenous; ABCB1 gene; ABC20; ABCB1; GP170; MDR-1; MDR1; MDR1 Protein; Multidrug Resistance 1; Multidrug Resistance Gene-1; Multidrug Resistance Gene-1s; Multidrug Resistance Proteins; Multidrug Resistant Proteins; P-GP; P-Glycoprotein; P-Glycoprotein 1 Gene; PGY-1 Protein; PGY1; programs; polyglutamine; Poly Q; polyQ; Inherited; Hereditary; Oral; System; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; autosome; mutant; neuron loss; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuroprotection; neuroprotective; Animal Model; Animal Models and Related Studies; model of animal; Stretching; Toxic effect; Toxicities; Histopathology; Cognitive deficits; cognitive defects; Modality; Gene Proteins; Protein Gene Products; Property; response; Huntington gene; HD Gene; HD protein; Huntingtin; Huntingtin Protein; Huntington protein; Huntington's disease gene product; IT15 gene; interesting transcript 15; Therapeutic Uses; preventing; prevent; small molecule; Length; Dose; Symptoms; ADME Study; Absorption, Distribution, Metabolism, and Excretion Study; Motor; in vivo; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; safety study; Pathway interactions; pathway; pre-clinical; preclinical; designing; design; neural dysfunction; Neuronal Dysfunction; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; CAG trinucleotide repeat; CAG repeat; Prevalence; NH2-terminal; N-terminal; innovate; innovative; innovation; murine model; mouse model; gain of function; therapeutic target; iPS; iPSC; iPSCs; induced pluripotent cell; inducible pluripotent stem cell; induced pluripotent stem cell; commercialization; discover genes; gene discovery; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; effective treatment; effective therapy; efficacy testing; drug candidate; screenings; screening; potential biological marker; potential biomarker; curative intervention; curative therapeutic; curative therapy; curative treatments; clinically translatable; clinical translation; in vivo testing; in vivo evaluation; safety assessment; PK/PD; pharmacokinetics and pharmacodynamics; Prognosis
