The excitement and precautions of clinical use of iPSCs

An Eureka blog by Mariangela Iovino in March of 2018 described the maturing field of iPSCs since its first discovery by Shinya Yamanaka back in 2006 with the tantalizing prospect of supporting new drug discovery and development. Equivalent to embryonic stem cells (ESCs), iPSCs have indefinite proliferative capacities while preserving pluripotency in order to differentiate into all known cell types. In addition, iPSCs can be generated from adult somatic cells by reprogramming without any controversial ethical issues surrounding ESCs.

Therefore, the clinical application of iPSCs represents a great promise in regenerative medicine. In December 2019, NIH launched the first US clinical trial of patient-specific iPSC-derived cell therapy to treat geographic atrophy, the advanced “dry” form of age-related macular degeneration (AMD), a leading cause of vision loss among people age 65 and older. This is certainly an exciting step forward to fulfill the full potential of iPSCs.

The potential safety concerns for iPSCs-derived cell therapies are tumorigenicity and immunogenicity. Tumorigenicity could arise due to any residual undifferentiated iPSC present in the final cell therapy product or when transplanted iPSCs-derived cell therapy products become unstable during the in vitro manufacturing process. The transcription factors and/or delivery methods of such factors for reprogramming of iPSCs are believed to have the major impact on iPSCs-based tumorigenicity. It has been shown that “integration-free” methods to deliver “right” sets of transcription factors can reduce the risk of tumorigenicity.

Even though in theory there is no risk of immunogenicity for autologous iPSCs-derived cell therapy products, immune rejection unfortunately has been reported after injection of such product. It is believed that the types of adult somatic cells, from which iPSCs are derived, as well as the reprogramming methods used to generate iPSCs are the potential culprits for the observed immunogenicity.

Recently a “universal” iPSC was generated by applying Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing technology in order to inactivate major histocompatibility complex class I and II genes, and also to overexpress the CD47 gene. As a result, hypoimmunogenic derivatives of such “universal” iPSC can evade immune rejection in fully immunocompetent allogeneic recipients.

In order to support clinical use of iPSCs as a starting material to generate cell therapy product, it is critical to generate clinical-grade iPSC cell banks following cGMP manufacturing process and quality control guideline. A White Paper published by Regenerative Medicine summarizes an international consensus of critical quality attributes (CQAs) and minimum testing requirements for clinical-grade iPSC cell banks. The suggested CQAs include identity, sterility, endotoxin, genetic fidelity & stability, viability, characterization, and potency. Various analytical methods can be used to evaluate the CQAs.

Additional technology, process, and analytical method improvement, including but not limited to automation, closed system, and validated testing methods, would be required to fulfill the full potential of iPSCs in fast-moving cell therapy field. Future is bright.