Innovative gene and cell therapy approaches are gaining momentum for hard-to-treat diseases. Lexeo Therapeutics and Tenaya Therapeutics pursue AAV-based gene therapies targeting inherited cardiovascular conditions via gene replacement in heart muscle cells. Vir Biotechnology has initiated trials for novel PRO-XTEN masked T-cell engagers in multiple solid tumors, including colorectal and lung cancers, with expected clinical milestones approaching. Concurrently, epigenome editing technologies, especially CRISPR-based modalities, are advancing toward clinical use to modulate gene expression for cancer and regenerative applications. These developments signify diversification and maturation of gene therapy modalities addressing complex diseases.