Parkinson's Disease (PD) is the second most common neurodegenerative disorder, afflicting ~1 million Americans. Levodopa is the gold-standard symptomatic treatment for PD by elevating dopamine levels in the brain. Though the most effective treatment, prolonged levodopa use leads to 1) the debilitating side effect, levodopa-induced dyskinesia (LID), and 2) diminished levodopa efficacy which leads to fluctuations of PD symptoms, known as "wearing-off". These concerns are two of the greatest unmet needs in PD and affect how doctors prescribe dosages and treatment options, impacting the efficacy of the necessary medications for PD. After 5 years of levodopa usage, 40% of PD patients will develop LID and/or fluctuations. Not only having a clinical impact, but PD patients with such complications require nearly $60,000 of additional therapeutics every year. Using Sinopia Biosciences' computational platform, we studied gene expression changes due to levodopa administered to 6-OHDA lesioned PD-like mice. Applying our computational workflow, we identified a small molecule (SB-0107) that was selected based on: 1) having one of the top scores from our platform, 2) its novel mechanism of action, 3) previous clinical exposure to elderly patients, 4) its predicted CNS penetration properties, and 5) its potential for patent protection. Subsequently, we demonstrated the compound's unique and potentially transformative pharmacology for treating both the symptoms of PD and complications of levodopa (i.e. LID). In both rodent and primate models, SB-0107 shows large effect sizes. Further, we observed in a cognitive deficit primate model of PD that SB-0107 improves performances in the tested cognitive tasks. Thus, SB-0107 represents a promising candidate for advancement to the clinic for PD. In this Fast-Track proposal, we will advance the compound by completing preclinical development studies for anticipation of IND submission.
Public Health Relevance Statement: Project Narrative Levodopa is the primary treatment for Parkinson's Disease, a neurodegenerative disease that afflicts 1 million Americans. Unfortunately, levodopa has serious side effects and loses its efficacy over time. Using Sinopia Biosciences's computational drug discovery platform, we identified a small molecule that we subsequently tested and validated in relevant rodent and primate models, providing a unique mechanism for treating Parkinson's Disease. This proposal will complete preclinical drug development for this compound in order to advance to the clinic.
Project Terms: Affect; inhibitor/antagonist; inhibitor; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Brain; Brain Nervous System; Encephalon; Climacteric; life change; Discrimination; Cognitive Discrimination; Disease; Disorder; Dopamine; Hydroxytyramine; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Gene Expression; Germany; Gold; Half-Life; Human; Modern Man; In Vitro; Levodopa; L-Dopa; Literature; Metabolism; Intermediary Metabolism; Metabolic Processes; Liver Microsomes; Mus; Mice; Mice Mammals; Murine; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Parkinson Disease; Paralysis Agitans; Parkinson; Parkinson's disease; Parkinsons disease; Primary Parkinsonism; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Pharmacology; Primates; Primates Mammals; Rattus; Common Rat Strains; Rat; Rats Mammals; Rodent; Rodentia; Rodents Mammals; Safety; Surveys; Survey Instrument; Testing; Time; Toxicology; Oxidopamine; 6-OHDA; 6-hydroxydopamine; Case Study; case report; Data Set; Dataset; base; dosage; improved; Acute; Chronic; Clinical; Penetration; Phase; Link; Lesion; disability; Funding; Agonist; MPTP Poisoning; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Poisoning; MPTP Neurotoxicity Syndrome; MPTP injury; MPTP lesion; MPTP lesioning; MPTP neurotoxicity; MPTP toxicity; MPTP-Induced Parkinsonism; toxic effects of MPTP; Therapeutic; Exposure to; machine learned; Machine Learning; Clinic; Pattern; 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; Neurodegenerative Disorders; meetings; American; Performance; mGluR4; metabotropic glutamate receptor 4; cognitive defects; Cognitive deficits; novel; behavioral test; behavior test; Position; Positioning Attribute; Gene Expression Monitoring; Gene Expression Pattern Analysis; Transcript Expression Analyses; Transcript Expression Analysis; gene expression analysis; gene expression assay; transcriptional profiling; Gene Expression Profiling; Modeling; Property; response; drug discovery; Neural Stem Cell; neural precursor; neural precursor cell; neural progenitor; neural progenitor cells; neuron progenitors; neuronal progenitor; neuronal progenitor cells; neuronal stem cells; neuroprogenitor; nerve stem cell; small molecule; Dose; Symptoms; Data; Pre-clinical Drug Testing/Development; Preclinical Drug Testing/Development; pre-clinical drug development; Preclinical Drug Development; Motor; in vivo; Pharmacological Treatment; Cardiac; Adjuvant; Development; developmental; preclinical study; pre-clinical study; Gene Expression Profile; Expression Signature; gene expression pattern; gene expression signature; transcriptional profile; transcriptional signature; older patient; elderly patient; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; effective therapy; effective treatment; preclinical efficacy; pre-clinical efficacy; candidate selection; L-DOPA induced dyskinesia; Levodopa dyskinesia; levodopa induced dyskinesia; Secure; cognitive testing; cognitive assessment; cognitive task; symptom treatment; symptomatic treatment; treat symptom; motor symptom; efficacy study; clinical development; preclinical development; pre-clinical development; computational platform; computing platform; side effect; motor behavior
