UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON
Cellular transplantation of lung stem/progenitor cells represents a potential therapeutic approach for a variety of inherited lung diseases. Crucial to the success of such a therapeutic strategy is that the transplanted cells and their progeny are corrected (both genotypically and phenotypically) for the disease-causing mutation and that the transplanted cells do not elicit an immune response in the recipient. Recently developed methodologies for generating induced pluripotent stem (iPS) cells and zinc finger nuclease (ZFN)-mediated genome editing make possible, in principle: a) the generation of autologous, patient-specific iPS cells carrying inherited genetic mutations; b) specific correction of the responsible genetic mutation in chromosomal DNA of the autologous iPS cells, and c) in vitro differentiation of iPS cells into various cell types required for cell transplantation therapy. We propose to employ this approach to generate corrected, autologous iPS cells for patients with either Surfactant Protein B (SP-B) Deficiency or Cystic Fibrosis (CF). For SP-B deficiency we will further generate corrected lung progenitor cells (lung alveolar epithelial type II cells; ATII) with the potential for cellular therapy of patients with this disease. This potentially high-impact two year project brings together the complementary expertise of two highly qualified principal investigators: one (Brian R. Davis) experienced in the generation/characterization of iPS cells together with ZFN-mediated genome editing, the other (Rick A. Wetsel) experienced in directed, in vitro differentiation of human pluripotent stem cells to lung progenitor cells and transplantation of such progenitor cells into mouse lung. This novel convergence of methodologies represents a paradigm applicable to cellular therapy of other single-gene caused diseases of the lung, heart, and blood systems. The objective of this project is to generate corrected, patient-specific lung progenitor cells for cell transplantation therapy of patients with inherited lung disease. It represents a novel convergence of methodologies for generation of autologous, pluripotent stem cells from somatic cells, efficient site-specific correction of genetic mutations in chromosomal DNA, and directed differentiation of pluripotent cells to cell types appropriate for transplantation.