Genetic Variations in the P2X7 Receptor: Opportunities and Challenges for Drug Development.

The P2X7 receptor (P2X7R) is a ligand-gated, non-selective cation channel activated by extracellular ATP, a key danger signal in the cellular stress response. Due to its roles in inflammation and neurological disorders, it is an attractive therapeutic target. However, clinical trials of P2X7R antagonists have failed to show clinical efficacy. This review explores whether receptor polymorphisms, alternative splicing, and membrane composition contribute to these clinical trial failures. Genotyping of trial participants is highly recommended prior to enrolment, and in vitro functional studies should be wary of the membrane composition of cells expressing P2X7R. While the P2X7R shows promising therapeutic potential, there remain large gaps in research particularly in characterising haplotypes and alternatively spliced hetero- or homotrimers of the receptor. This results in the development and testing of agents without considering the genetic variability of the receptor, which we propose to be a large contributor to the lack of clinical success. We also summarise characteristics of the receptor and recent structural findings to discuss how computational approaches may help overcome these challenges of variability. Precision targeting of the receptor in disease states is warranted, and a collaborative approach covering multiple facets of the receptor will facilitate this.