In one famous example, multiple studies have shown that replacing SMN1 gene in treating spinal muscular atrophy (an approved gene replacement therapy indication 5 years ago) exhibited the gain of toxic function by long-term sustained overexpression of neuronal proteins SMN in the sensorimotor circuit, which is not due to the use of AAV vectors48,49. This evidence concerns the gene SMN1 and proximal spinal muscular atrophy.