Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the life-limiting hereditary disease, cystic fibrosis (CF). Decreased or absent functional CFTR protein in airway epithelial cells leads to abnormally viscous mucus and impaired mucociliary transport, resulting in bacterial infections and inflammation causing progressive lung damage. There are more than 2000 known variants in the CFTR gene. A subset of CF individuals with specific CFTR mutations qualify for pharmacotherapies of variable efficacy. These drugs, termed CFTR modulators, address key defects in protein folding, trafficking, abundance, and function at the apical cell membrane resulting from specific CFTR mutations. However, some CFTR mutations result in little or no CFTR mRNA or protein expression for which a pharmaceutical strategy is more challenging and remote. One approach to rescue CFTR function in the airway epithelium is to replace cells that carry a mutant CFTR sequence with cells that express a normal copy of the gene. Cell-based therapy theoretically has the potential to serve as a one-time cure for CF lung disease regardless of the causative CFTR mutation. In this review, we explore major challenges and recent progress toward this ambitious goal. The ideal therapeutic cell would: (1) be autologous to avoid the complications of rejection and immune-suppression; (2) be safely modified to express functional CFTR; (3) be expandable ex vivo to generate sufficient cell quantities to restore CFTR function; and (4) have the capacity to engraft, proliferate and persist long-term in recipient airways without complications. Herein, we explore human bronchial epithelial cells (HBECs) and induced pluripotent stem cells (iPSCs) as candidate cell therapies for CF and explore the challenges facing their delivery to the human airway.
Highlights
Cystic fibrosis (CF) is an autosomal recessive, multisystem, genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in deficient and/or defective CFTR protein (Cutting, 2014; Ratjen et al, 2015)
We review the essential studies that made the discovery of induced pluripotent stem cells (iPSCs) possible, summarize the recent progress in deriving lung epithelial cells from iPSCs (Table 1), cell types relevant to CF, and highlight the many challenges to be addressed before these cells can be transplanted into CF recipients
Crucial to the emerging field of regenerative medicine, iPSCs have four key characteristics: (1) they are generated from the potential recipient, i.e., autologous, (2) they provide an unlimited supply of pluripotent stem cells without the need for embryonic tissues, (3) they are amenable to gene correction approaches, and (4) they are routinely derived
Summary
Cystic fibrosis (CF) is an autosomal recessive, multisystem, genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in deficient and/or defective CFTR protein (Cutting, 2014; Ratjen et al, 2015). Some variants are associated with milder disease or particular organ involvement while others may be associated with very severe disease For classification purposes, these mutations are grouped into six classes (I-VI) based on their effect on CFTR including: no protein synthesis (class I), protein misfolding (class II), dysfunctional channel gating (class III), reduced conductance (class IV), insufficient CFTR protein due to abnormal RNA splicing (class V), or increased protein turnover (class VI). Class I mutations are non-sense, frameshift or splice variants that result in premature termination of the CFTR transcript and no CFTR protein These patients currently have no targeted therapies available and there are many barriers to a pharmacological approach to treatment. There are compelling examples of effective cell-based therapies, such as hematopoietic stem cell transplantation, there are many challenges facing such an approach for lung disease. We will discuss the major hurdles facing the field of CF cell-based therapeutics, including delivery and engraftment of cells into a diseased host
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