GENE EDITING IN PERSONALIZED MEDICINE: TRANSFORMATIVE POTENTIAL AND REMAINING CHALLENGES

Gene editing has become one of the most disruptive innovations in contemporary biomedicine. This tool not only opens opportunities for developing new therapeutic options for monogenic and polygenic diseases but is also transforming the way genetic disorders are diagnosed. Its appeal lies in progressively reduced costs and increasing technical feasibility, which explains its rapid expansion in clinical and preclinical research worldwide. Several gene-editing systems have been developed in recent decades. Among them are meganucleases, zinc-finger nucleases (ZNF), transcription activator-like effector nucleases (TALE), and, most notably, the CRISPR/Cas9 system (clustered regularly interspaced short palindromic repeats / CRISPR-associated protein 9). The CRISPR/Cas9 system originated from a natural bacterial and archaeal defense mechanism that provides resistance to viral infections. Its basic architecture consists of two key components: an endonuclease (Cas9) and a single-guide RNA (sgRNA) that directs the cut to a specific genomic region (1). The versatility of this system enables multiple applications, including gene regulation, visualization of specific genomic regions, induction of epigenetic modifications, and, more recently, its incorporation into therapeutic strategies (1). In gene therapy, two main approaches are distinguished: germline gene therapy (GGT) and somatic cell gene therapy (SCGT) (2). The former targets germ cells, meaning that the modifications are heritable, while the latter focuses on correcting abnormalities in non-germline cells. In the case of SCGT, the procedure is typically performed ex vivo, followed by reinfusion of the corrected cells into the patient (2). Currently, numerous clinical trials are evaluating the safety and efficacy of these approaches. Notable studies in monogenic diseases include those addressing Duchenne muscular dystrophy, congenital cataracts, cystic fibrosis, hereditary tyrosinemia type 1, urea cycle disorders, retinitis pigmentosa, and Down syndrome (3, 4). At the same time, applications are being explored in complex diseases such as cancer, high-burden infections (e.g., HIV and malaria), and kidney transplantation contexts (4). A landmark achievement has been the recent approval by the FDA (Food and Drug Administration), EMA (European Medicines Agency), and MHRA (UK Medicines and Healthcare Products Regulatory Agency) of exagamglogene autotemcel (Casgevy®) for transfusion-dependent patients with sickle cell disease and β-thalassemia (5, 6). This milestone marks the transition of gene editing from research to clinical practice.