Core Viewpoint - The article highlights the significant advancement in personalized medicine through the successful application of a bespoke CRISPR gene editing therapy for a patient with a severe genetic disorder, marking a milestone in individualized treatment approaches [2]. Group 1: Personalized CRISPR Therapy - The first patient to receive a personalized CRISPR gene editing therapy was diagnosed with carbamoyl phosphate synthetase 1 (CPS1) deficiency shortly after birth, and researchers developed a tailored lipid nanoparticle (LNP) delivery system for the therapy within six months, leading to substantial clinical improvement [2]. - The success of this case serves as a paradigm for personalized therapies, showcasing the potential of CRISPR technology in treating various devastating diseases, including vascular disorders [2]. Group 2: Research on Vascular Disease - A study published by researchers from Harvard Medical School and Massachusetts General Hospital demonstrated the successful treatment of a severe vascular disease, multi-system smooth muscle dysfunction syndrome (MSMDS), using a customized CRISPR-Cas9 base editor in mouse models [3][4]. - MSMDS, characterized by mutations in the ACTA2 gene, currently lacks effective treatment options, with the most common mutation being a G to A single nucleotide change at the sixth exon of the ACTA2 gene [7]. Group 3: Development of Targeted Therapy - The research team identified that conventional adenine base editors (ABE) could cause "bystander editing," leading to ineffective treatment outcomes. Therefore, they developed a personalized therapy targeting the most common pathogenic mutation, ACTA2 R179H, by screening for a SpCas9 enzyme with enhanced targeting specificity [9]. - An engineered SpCas9-VRQR was successfully constructed, allowing for precise A to G editing while minimizing unintended edits, thus improving the efficacy of the base editor [9]. Group 4: Efficacy in Mouse Models - The team created a mouse model that exhibited phenotypes consistent with human patients, including vascular lesions and early mortality, to explore the in vivo therapeutic potential of their strategy [10]. - The use of an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector to deliver the customized base editor resulted in significantly extended lifespans for MSMDS mice and rescued systemic phenotypes throughout their lifetimes [10]. Group 5: Regulatory Progress and Future Trials - The developed therapy has received orphan drug designation from the FDA for rare diseases, and the research team plans to conduct further toxicology studies, with the aim of initiating human trials by 2027 [13].