NETSseq Identifies Novel Therapeutic Targets for Neurodegenerative Diseases
Mark Carlton1, Xiao Xu1, Giuliano Stirparo1, Marina Lizio1, Justin Powell1, Toni Thompson1, David Cadwalladr1, Jason Lawrence1, Steven Sheardown1, Bernadino Ossola1, Louise Dickson1, Keith Page1, Nicola Brice1, Lee Dawson1
1Cerevance Ltd
Objective:

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

Background:

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.

Design/Methods:

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.

Results:

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). 

Assessment of cortical substructures from AD donors identified that the 2-pore potassium channel KCNK13 is specifically expressed in microglia and increases with disease progression. KCNK13 is a novel modulator of the NLRP3-inflammasome proinflammatory response pathway and attenuates the inflammation seen across neurodegenerative diseases. These findings led us to develop CVN293, an investigational inhibitor of KCNK13 (Burli et al 2024) which recently completed its Phase 1 study. 
Conclusions:
In conclusion, NETSseq has the potential to identify cell specific gene targets and biological insight into human brain disorders, which can be developed into novel therapies for neurodegenerative diseases.
10.1212/WNL.0000000000211104
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.