Center for Fetal Money Gene Transfer for HLB Diseases

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DESCRIPTION (provided by applicant): The intent of this proposal is to establish a Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases. The immediate goal of this Center is to explore critical issues for in utero gene transfer in the rhesus monkey model, which closely simulates humans. We propose that performing gene transfer prenatally will provide the best opportunity for eliminating the pathology associated with many life-threatening congenital conditions because delivery of a corrective gene early is likely to prevent damage in organs or cells inaccessible later in life. However, before considering application for human fetuses, it is essential that issues such as cell tropism, levels and duration of gene expression, and safety be addressed in relevant animal models such as the monkey. Our first Objective is to investigate the efficiency of recombinant viral vector systems in transferring genes into fetal rhesus monkeys in vivo for cardiac, pulmonary, and hematopoietic disorders. In Objective 1, Specific Aim 1, we will explore the efficiency of transduction of two integrating viral vector systems, self-inactivating HIV-1-derived lentivirus and adeno-associated virus (AAV), using systemic and organ-targeting approaches. In these studies, constitutive and cell-specific promoters will be used, and we will transfer viral vector constructs into fetal monkeys at defined gestational ages and based on developmental milestones. In Specific Aim 2 of this Objective, we will determine whether immune responses are generated to transgene products and/or vectors, and confirm that organ structure and postnatal function is not altered as a result of our prenatal interventions. Our second Objective focuses on providing specialized services to NHLBI-funded investigators for fetal gene transfer for heart, lung, or blood diseases. In Objective 2, Specific Aim 1, we will provide our unique primate expertise, services, and resources to NHLBI-funded investigators who wish to evaluate their viral and non-viral gene transfer strategies in monkeys. In order to effectively provide these services, Specific Aim 2 of this Objective includes a plan for administrative/scientific oversight, a Scientific Advisory Committee, and outreach efforts for NHLBI-funded investigators. We propose that by establishing the Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases we will be able to explore the efficiency of gene transfer strategies as they emerge, fully investigate the potential effects of gene transfer on the fetus, infant, and mother, and significantly advance the field of gene therapy for future human application.