Genetic Medicine Approaches for Tumor Suppressor Loss: Therapeutic Replacement with Self-Amplifying RNA

Deletion or functional inactivation of tumor suppressor genes is a hallmark of human cancers. Unlike hyperactive oncogenes, which produce proteins that are targetable through pharmacologic inhibition, treatments to restore tumor suppressor protein activity are challenging given the loss-of-function nature of tumor suppressors. Current replacement-based strategies to re-establish tumor suppressor function using viral vectors and non-amplifying RNA therapeutics are fraught with challenges, including transient and/or insufficient expression of the restored tumor suppressor protein. In this Review, we highlight self-amplifying RNA (saRNA) as a next-generation platform for tumor suppressor restoration. saRNA enables intracellular RNA amplification and prolonged protein expression at lower doses while avoiding genomic integration, potentially overcoming key limitations of existing replacement approaches. Furthermore, by integrating genomic recurrence, delivery feasibility, construct constraints, and pathway biology, we describe a translational prioritization framework to identify tumor suppressors best suited for saRNA-based replacement, with particular emphasis on cancers harboring recurrent homozygous deletions. Effective restoration of tumor suppressor protein activity using saRNAs will open new avenues for cancer therapeutics.