Gene Transfer to Progenitor and Differentiated Cells

Crystal, Ronald

Abstract

This Program Project is directed toward the challenge of transferring genes to progenitor and differentiated cells relevant to disorders of the heart, lung, and blood, a challenge that can be successfully overcome ony by under-standing the biology of gene transfer to these target cells, and the consequences of modifying the genetic reper-toire of one or more cell types in the relevant target organs. To accomplish this, the Program Project is con-structed to bring together senior investigators at CUMC, SKI, and The Rockefeller University with overlapping interests in gene transfer to progenitor and differentiated cells, and focus the activities o their laboratories, to-gether with existing gene therapy core facilities, towards and integrated effort relevant to gene therapy of disor-ders of the heart, lung and blood. The program Project is comprised of five projects, six core laboratories, and two pilot projects. The five projects include: (1) studies of the regulation of cardiac myocyte cell division in the embryo relevant to gene therapy in the adult myocardium: (2) gene transfer to hematopoietic progenitor cells to stimulate stem cell and lineage-specific growth and differentiation: (3) the biology of gene transf to precursor, resting and activated alveolar macrophages: (4) the biologic determinants of gene transfer to hematopoietic pro-genitor cells, with a focus on transcriptional and chromatin determinants relevant to long term expression in the context of a housekeeping gene (G6PD) that may confer selective growth advantage to genetically corrected cells in the deficient host; and (5) the development of a chimeric gene transfer system, relevant to progenitor and differentiated cells, that combines the advantages of effective transient gene transfer with adenovirus vectors and the integrating potential of adeno-associated virus. The four core laboratories all established, include: Core A - DNA viral vectors (adenovirus, adeno- associated virus, herpesvirus); Core B - retrovirus vectors; Core C - cell biology; Core F - administration. The two pilot projects (Core G) include: pilot 1- angiogenesis in the central nervous system for the prophylaxis and therapy of stroke; and Pilot 2-adeno-associated virus vectors coding for apolipoprotein E (apoE) to modulate cholesterol metabolism and central nervous system adnormalities in apoE deficient mice.