Study Rationale: Understanding neurological conditions has been among the most difficult challenges in modern medicine. The brain contains more than 86 billion nerve cells that form the neural circuits responsible for our thoughts, feelings, and actions. Altering the function of these circuits in a targeted manner in individuals with brain disorders is a complex endeavor, and the field has seen little innovation in the advancement of effective therapies. At MapLight, we are using several cutting-edge technologies to identify the neural cell-types and circuits that mediate disease symptoms and to identify and measure the activity of target genes within these specific cell classes.
Hypothesis: We hypothesize that using a combination of optogenetics, single-cell RNA sequencing and spatial transcriptomics we can identify target genes and develop novel compounds for the treatment of Parkinson’s disease (PD).
Study Design: Using MapLight’s platform, we determined that a G protein-coupled receptor protein called GPR6 is restricted almost entirely to a neuronal circuit that helps to prevent unwanted, involuntary muscle contraction. We confirmed the specificity of this distribution in brain tissue from both rodents and humans. We then identified compounds that reduce the activity of this receptor and performed preclinical validation of these compounds for treating both PD and depression. In this study, we build on these discoveries by expanding our medicinal chemistry program to identify novel lead compounds and undertaking additional validation studies.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this project will provide a novel, targeted approach to controlling the unwanted, involuntary movements associated with PD.
Next Steps for Development: At the conclusion of the project, MapLight will scale production of the lead compound, perform IND-enabling studies and conduct clinical trials to advance our candidate to market.