Table 1.

Concerns and countermeasures

	(A) Types of Concern	(B) Measures Taken		(C) Counterarguments
Tumorigenicity	Use of viral vectors that integrate inserted genes into the host genome, thereby causing mutations and encouraging tumorigenic gene expressions	To use non-integrative cell reprogramming method using episomal vectors containing Epstein-Barr-virus (EBV) -based plasmids, which remain in the host cell for 10–14 days for the cell-reprogramming purpose but gradually disappear after multiple cell divisions	Tumorigenicity tests in animals	■ Undeniable chance of integration of a small percentage of plasmids into host genome ■ Oncogenic potential of wile-type woodchuck hepatitis post-transcriptional regulatory element (WPRE), a fragment encoded in the plasmid to facilitate strong expression of reprogramming genes ■ Possible cell proliferation encouraged by the EBV nuclear antigen 1 (EBNA1) gene, which is indispensable for temporal bindings of plasmids to the host chromosomes ■ Tumorigenicity risks unrelated to genomic insertion being unresolved
	Use of oncogenic transcription genes	To substitute c-Myc with alternative factors
	Malignant transformation of residual undifferentiated cells	To purify RPE cells to eliminate undifferentiated low-grade cells; to conduct product inspection
	Reactivation of tumorigenic network in differentiated RPE cells	To create an RPE sheet so that the differentiated cells remain stable and hard to transform
	Immunosuppression encouraging tumor formation	Autologous transplant that may reduce the risk of immune rejection		■ Fundamental question about inherent tumorigenic potential of iPSCs
				■ Possibility of contamination not being ruled out ■ Possibility of de-differentiation of injected cells into tumorigenic immature cells due to microenvironment in vivo
				■ Limited data of macaque monkeys at presentLikelihood and degree of immune rejection yet to be investigated
Graft survival	Immune rejection	Same as above		Same as above
	Low-efficiency in survival of graft cells			■ The more differentiated, the harder the graft cells tend to survive in vivo
Others	Risks associated with eye surgery (retinal detachment, etc.)
	Viral infection caused by contaminated graft cells	Manufacture in compliance of Good Manufacturing Practice
	Others