Pluripotent stem cell applications for regenerative medicine

Abstract

Purpose of review: In this review, we summarize the current status of clinical trials using therapeutic cells produced from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). We also discuss combined cell and gene therapy via correction of defined mutations in human pluripotent stem cells and provide commentary on key obstacles facing widescale clinical adoption of pluripotent stem cell-based therapy.

Recent findings: Initial data suggest that hESC/hiPSC-derived cell products used for retinal repair and spinal cord injury are safe for human use. Early-stage studies for treatment of cardiac injury and diabetes are also in progress. However, there remain key concerns regarding the safety and efficacy of these cells that need to be addressed in additional well designed clinical trials. Advances using the clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9 gene-editing system offer an improved tool for more rapid and on-target gene correction of genetic diseases. Combined gene and cell therapy using human pluripotent stem cells may provide an additional curative approach for disabling or lethal genetic and degenerative diseases wherein there are currently limited therapeutic opportunities.

Summary: Human pluripotent stem cells are emerging as a promising tool to produce cells and tissues suitable for regenerative therapy for a variety of genetic and degenerative diseases.

FIGURE 1. Clinical strategy for wide-scale hiPSC-based gene and cell therapy

A. Dermal fibroblasts or peripheral mononuclear blood cells are obtained from patient with a defined genetic disease. hiPSCs are engineered from autologous cells via reprogramming with defined factors. Pathological mutations can be corrected through zinc-finger nucleases (ZFN), TAL effector nucleases (TALEN), or clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) gene-editing technologies. Gene-corrected hiPSCs can then be differentiated into the desired cell and/or tissue products prior to autologous transplantation via direct injection or seeding on a biocompatible scaffold. B. Prior to autologous cell transplantation, gene-corrected hiPSC-derived cell products must first pass several safety checkpoints, such as viral, toxicology, and tumorigenicity screens. Cells would also be immunophenotyped and banked for future patient use based on human leukocyte antigen (HLA) expression at this time. Furthermore, logistical hurdles such as obtaining intellectual property rights for product commercialization and regulatory agency approval must be in place prior to clinical trial.