Testicular mRNA-LNP Delivery: A Novel Therapy for Genetic Spermatogenic Disorders

The current paradigm for treating genetic spermatogenic disorders includes hormone therapy and microdissection testicular sperm extraction (micro-TESE), which offer limited success. Gene therapies, specifically using CRISPR/Cas9, have shown promise in preclinical models but face challenges regarding off-target risks, ethical concerns, and limited clinical translatability.

This preprint falls under the "Normal Science" stage of Kuhn's paradigm cycle. It operates within the existing paradigm of protein replacement therapy (PRT) for genetic disorders and explores mRNA-based delivery as a means of achieving transient protein expression in target cells. The study focuses on optimizing the delivery system using lipid nanoparticles (LNPs) and demonstrates its efficacy in restoring spermatogenesis in mouse models of genetic spermatogenic disorders. Although it introduces a novel LNP formulation with enhanced tropism for spermatocytes, it doesn't challenge the fundamental assumptions of PRT or propose a radical shift in understanding spermatogenic disorders. The research builds upon the existing knowledge base and refines established techniques, aligning with Kuhn's concept of "puzzle-solving" within a paradigm. The work's novelty lies in the optimized LNP design and its successful application to a specific therapeutic area, but it doesn't constitute a paradigm shift. It could however be considered to also fall under 'Model Drift' due to the refinement of current LNP technology for a novel application, and exploring the limitations of existing LNP constructs.