Roadmap to discovery and early development of an mRNA loaded LNP formulation for liver therapeutic genome editing.

Introduction: mRNA therapeutics were a niche area in drug development before COVIDvaccines. Now they are used in vaccine development, for non-viral therapeuticgenome editing, in vivo chimericantigen receptor T  (CAR T) celltherapies and protein replacement.  mRNAis large, charged, and easily degraded by nucleases. It cannot get into cells,escape the endosome, and be translated to a disease-modifying protein without adelivery system such as lipid nanoparticles (LNPs).

Areas covered: This article covers how to design, select, and develop an LNP fortherapeutic genome editing in the liver. The roadmap is divided into selectingthe right LNP in discovery via a design, make, test, analyze cycle (DMTA). Thedesign elements are focused on the ionizable lipid in a 4-component LNP, andinsights are provided for how to set an invitro and in vivo testingstrategy. The second section focuses on transforming the LNP into a clinicaldrug product and covers formulation, analytical development and processoptimization, with brief notes on supply and regulator strategies.

Expert opinion: The perspective discusses the impact thatacademic-industry collaborations can have on developing new medicine fortherapeutic genome editing in the liver. From the cited collaborations an enhancedunderstanding of intracellular trafficking, notably endosomal escape, and theinternal structure of LNPs were attained and are deemed key to designingeffective and safe LNPs. The knowledge gained will also enable additional assays and structure activity relationships, which wouldlead to the design of the next generation delivery systems for nucleic acidtherapies.