Germline gene therapy is controversial because:
Germline gene therapy introduces intentional genomic alteration into zygotes, totipotent embryonic stem cells, or gamete precursors contributing to both somatic tissues and gonadal germline, establishing heritable change transmitted through fertilization. Using CRISPR Cas9 ribonucleoprotein comprising guide RNA complementary to 20 bp target adjacent to PAM and Cas9 nuclease with HNH and RuvC domains, double-strand break created in totipotent cell repaired by homology-directed repair incorporating donor template correcting mutation throughout embryo. Every tissue including testes and ovaries carries edited allele, so children inherit modification. Controversy stems from inability to obtain consent from future generations, risk of off-target cleavage at homologous loci generating de novo mutations propagated indefinitely, potential mosaicism causing unpredictable phenotype, and concerns regarding eugenic enhancement, loss of diversity, and irreversible alteration of human gene pool. International documents Oviedo Convention, UNESCO Declaration, and FDA regulations prohibit clinical application, distinguishing ethical weight from somatic therapy limited to one person. This mechanistic insight guides vector optimization, dosing strategies, and clinical safety monitoring essential for translational development and regulatory evaluation.
Ref: Nature Rev Genet Germline Editing Ethics 2017; NIH StatPearls Germline Therapy; UNESCO Bioethics Declaration https://www.nature.com/articles/nrg.2017.52.