The development of a clinical grade method to efficiently generate genetically stable induced pluripotent stem cells (iPSC) and derived cells that engraft with no evidence of pathology remain key challenges to accurately model and reliably treat human disease with iPSC. To develop a clinical grade protocol we adopted a synthetic mRNA transfection method using clinical grade cell culture materials that is robust, efficient and maintains parental cell CNV. Human iPSC made with our new method and derived neural stem cells (iNSC) have significantly reduced genetic instability: (i) lower multi-telomeric signal, (ii) reduced double strand DNA breaks (DSB) measured by H2AX expression, (iii) correct nuclear localization of Rad51 protein expression and (iv) whole genome sequencing (WGS) reveals reduced DNA structural variations implicating less coamplifications of cancer genes. In vivo analysis demonstrates reduced teratoma growth and proliferative rate of our iPSC and iNSC. The iNSC derived from our iPSC engraft in a spinal cord injury microenvironment, have a high percentage of survival, differentiate properly to neurons, oligodendrocytes and astrocytes over time with no evidence of pathology. In conclusion, we have developed a method to generate iPSC to generate improved genetically stable iPSC and iNSC that we offer as a potential standard operating procedure (SOP) for future clinical applications to accurately model and treat human disease.