Patient-derived teratomas as a humanized platform for dystrophin restoration by ex vivo cell therapy and in vivo base editing

Abstract Cell and gene therapies hold great promise for treating monogenic disorders, yet their preclinical evaluation remains limited by the lack of scalable, human-specific models. Here we establish a patient-derived teratoma xenograft platform as a proof-of-concept system to evaluate ex vivo and in vivo therapeutic strategies for Duchenne muscular dystrophy (DMD). Teratomas generated from DMD patient-derived induced pluripotent stem cells contained mesodermal derivatives, including skeletal muscle-like tissue, enabling assessment of dystrophin restoration after therapeutic intervention. For ex vivo cell therapy, myogenic progenitors derived from adenine base editor-corrected induced pluripotent stem cells were transplanted into DMD teratomas, resulting in partial restoration of shorter dystrophin isoforms but not reproducible recovery of full-length Dp427m. For in vivo gene editing, local delivery of adenine base editor mRNA encapsulated in lipid nanoparticles induced dose-dependent editing and restoration of shorter dystrophin isoforms, including Dp71. Full-length, muscle-specific Dp427m was detected only in a subset of sequentially matured secondary teratomas with enriched muscle differentiation, indicating that myogenic maturation is a critical determinant of this therapeutic readout. Together, these findings support patient-derived DMD teratomas as an exploratory humanized platform for evaluating patient-specific gene correction and dystrophin isoform restoration, while highlighting the need for further optimization to reproducibly model full-length Dp427m recovery.