Abstract
The application of gene therapy to the treatment of human disease with complex etiology and pathology will often require the delivery of large payloads exceeding 10 kbp in size. This is generally not possible with the most popular vectors such as adeno-associated viruses (AAVs), lentiviruses (LVs), retroviruses (RVs), and many nonviral delivery systems. There is a high likelihood that the correction of many human gene defects such as those associated with neurodegenerative diseases and inflammatory processes will require single large genes or complex genetic payloads that will often necessitate precise regulatory control of the specificity, timing, and duration of corrective gene expression. The regulation of cellular gene products typically depends on genomic promoter systems and splicing-driven transcription variants, necessitating a delivery vector with substantial payload capacity. Replication-defective herpes simplex virus (rdHSV) mutants lack at least one essential viral gene product and are propagated in host cells that supply the missing gene product. This review explores next-generation rdHSV vectors, which do not express viral genes, offer high payload capacity, and can be engineered for safe, long-term transgene expression. These advanced vectors enable the correction of complex diseases affecting neurons and other tissues, paving the way for large or intricate gene replacement strategies.