Current progress in gene therapy, gene editing, and targeted therapeutics for disease cure and clinical management: Transformative advances of the past half-decade and beyond

The past decade has witnessed significant progress in gene therapy, gene editing, and targeted therapeutics, with applications in disease cure, precision therapy, and enhanced clinical management. Advances in CRISPR-Cas9, base and prime editing, next-generation viral and nonviral vectors, RNA therapeutics, and modulated immune-cell therapies have stimulated the transition from laboratory research to global clinical application. Concurrently, India has achieved notable progress with the development of its first indigenous Chimeric Antigen Receptor T-cell therapy (CAR-T) product (NexCAR19) and the introduction of a national sickle-cell anaemia elimination mission incorporating genetic and pharmacological interventions. This editorial has pinpointed both global and Indian milestones, highlighting the translational potential and future application of precision medicine. ADVANCES IN GENE THERAPY AND DELIVERY TECHNOLOGIES The past 15 years have marked a major turning point in the field of gene therapy. During this period, Adeno-associated viral (AAV) platforms have advanced substantially, with modified capsids, including AAV9 derivatives and AAVrh74, enabling enhanced biodistribution to the liver, central nervous system, and muscle.[1] These modifications facilitated approvals for haemophilia A and B, spinal muscular atrophy, inherited retinal dystrophies, and several metabolic disorders. Promoter and enhancer engineering additionally improved tissue specificity, reducing systemic toxicity. In parallel, advanced nonviral systems – lipid nanoparticles, polymeric carriers, and exosome-based delivery repeated dosing and expanded the treatable disease spectrum. These advances collectively bring gene therapy closer to safe, single-dose, long-term rectification of genetic disorders. CRISPR AND PRECISION GENOME EDITING EVOLUTION CRISPR-based treatment strategies have progressed remarkably, manifested in regulatory approval of Casgevy for sickle-cell disease and β-thalassemia, signifying durable hematopoietic stem-cell editing.[2] Base editing technologies achieved A→G and C→T conversions without causing double-strand DNA breaks,[3] thus lessening chromosomal rearrangements and genotoxicity. Prime editing added extra precision, enabling targeted sequence insertions and amendments across a varied mutational spectrum.[4] The first in vivo CRISPR therapeutic for transthyretin amyloidosis displayed persistent reduction of disease-causing protein following a single infusion.[2] Moreover, CRISPR interference (CRISPRi) and activation (CRISPRa) currently permit reversible modulation of gene expression, expanding therapeutic flexibility and safety, particularly for polygenic and epigenetic conditions. TARGETED THERAPEUTICS, RNA MEDICINES, AND MULTI-OMICS INTEGRATION RNA-centred therapy has become vital to modern molecular medicine. mRNA technology has been refined during the COVID-19 pandemic, which has extended into cancer neoantigen vaccines, protein-replacement strategies, and tolerance-inducing immunotherapies. siRNA and antisense therapeutics (such as inclisiran, patisiran, and inotersen) have revealed durable gene silencing in metabolic and amyloid disorders. Integrating these technologies, multi-omics innovations – single-cell RNA sequencing, spatial transcriptomics, proteogenomics, and artificial intelligence-guided target invention – have deeply apprised drug-development pipelines.[5] These explorations have shown tumor heterogeneity, therapy-resistant subclones, and microenvironmental vulnerabilities, enabling precision therapeutics including KRAS G12C inhibitors, PARP inhibitors for BRCA-mutant cancers, IDH inhibitors, and JAK-STAT/PI3K-targeted agents. ENGINEERED IMMUNE-CELL THERAPIES AND INDIA’S TRANSLATIONAL BREAKTHROUGHS Cellular therapies have grown vastly. CAR-T cells have changed from initial CD19-targeting constructs to advanced “armored” CAR-T systems capable of secreting cytokines and resisting tumor-microenvironment suppression. Dual-antigen CAR-T therapies reduce antigen escape, and CRISPR-edited allogeneic CAR-T and CAR-NK therapies are budding as scalable, off-the-shelf solutions. Food and Drug Administration-approved BCMA-directed products, idecabtagene vicleucel and ciltacabtagene autoleucel, have yielded exceptional responses in relapsed multiple myeloma.[6] India has achieved a breakthrough with NexCAR19, its first indigenous CAR-T therapy developed by IIT Bombay and ImmunoACT. NexCAR19 is completely manufactured in India, presenting a major progression toward inexpensive immunotherapy and demonstrating the country’s translation capability.[7] India’s National Mission to Eliminate Sickle Cell Anaemia (2023–2030) further highlights this development. Through large-scale screening, indigenous vector manufacturing, lentiviral HBB gene-addition strategies, and CRISPR-based fetal hemoglobin reactivation programs, agencies including CSIR-IGIB, ICMR, and DBT have placed India among countries developing sovereign gene-therapy pipelines.[8,9] Complementary therapies such as voxelotor and crizanlizumab further strengthen clinical care pathways. SAFETY, REGULATION, AND FUTURE DIRECTIONS Progression in biosafety and regulation has been vital to the translation of gene and cell therapies. Capsid de-immunization approaches mitigate preexisting neutralizing antibodies, and organ-specific promoters increase the predictability of gene expression. Machine-learning tools now support off-target prediction for genome-editing technologies. Indian initiatives, including DBT-BIRAC-supported GMP units, have reinforced domestic manufacturing capacity. Overall, the rapid developments of the past half-decade have built a strong technological and regulatory groundwork for the next era of personalized genomic medicine.