From SELEX to the Clinic: Evolution, Engineering, Manufacturing and Clinical Translation of Therapeutic Aptamers

Abstract

With advances in selection technologies, molecular engineering, chemical modifications, and delivery approaches enhancing their therapeutic capabilities, therapeutic aptamers represent an emerging class of molecular recognition compounds. Advances in aptamer technology from conventional Systematic Evolution of Ligands by EXponential Enrichment (SELEX) to advanced SELEX platforms, including cell-SELEX, tissue-SELEX, in vivo SELEX, microfluidic SELEX, capillary electrophoresis-SELEX, and modified nucleotide SELEX, are described in this review. Aptamer identification, optimization, conjugation, engineering of structure and chemistry, and generation and characterization of therapeutic candidates are also described. Through analysis of the approved, suspended, discontinued, and current therapeutic efforts and the factors that shape them, a particular emphasis on the clinical application of aptamers is provided.Also discussed are issues related to regulation and CMC considerations, which include manufacturing consistency, stability, chemical modifications, and quality. Finally, innovative approaches to improving the effectiveness of selection process, physiological relevance, and clinical translation are reviewed, which include next generation sequencing, bioinformatics, artificial intelligence, microfluidic automation, and engineering. In summary, next generation development of therapeutic aptamers could benefit from the advancement of translational development, molecular engineering, and selection approaches.