To identify cell type specific targets from human brain with relevant, modulatory functions, as novel therapeutic approaches to treat neurological diseases.

Neurodegenerative diseases remain a major challenge for drug discovery. To identify new, disease modifying treatments, an integrated understanding of individual cell types, their function and how their properties change during human disease is required.

Using Nuclear Enriched Transcript Sort sequencing (NETSseq) and post-mortem human brain samples from Alzheimer’s disease (AD), Parkinson’s Disease (PD) and non-neurodegenerative disease control donors, we have produced deep transcriptomic (usually encompassing approximately 12,000 genes) profiles for glial and neuronal cell types (~60), across multiple brain structures. Machine learning methodologies were used to identify cell specific genes that can modulate specific circuits, or that change with disease.

Here, we present two clinical-stage novel therapeutic targets with specific expression in the human brain.

Assessment of striatal tissues revealed the specific expression of the orphan G-protein coupled receptor (GPCR), GPR6, in the dopamine receptor (DRD2) expressing indirect median spiny neurons. Based on the highly specific localisation and the biological function of GPR6 in models of PD, we developed solengepras (CVN424), which in a Phase 2 study was demonstrated to be generally well-tolerated and provided clinically meaningful activity in PD (Brice et al 2022/2024).