Efficient Early and Sustained Transduction of Human Fetal Mesencephalon Using Adeno-Associated Virus Type 2 Vectors
Abstract:The success of transplantation of human fetal mesencephalic tissue into the putamen of patients with Parkinson’s disease (PD) is still limited by the poor survival of the graft. In animal models of fetal transplantation for PD, antiapoptotic agents, such as growth factors or caspase inhibitors, or agents counteracting oxidative stress enhance the survival and reinnervation potential of the graft. Genetic modification of the transplant could allow a local and continuous delivery of these factors at physiologically relevant doses. The major challenge remains the development of strategies to achieve both early and sustained gene delivery in the absence of vector-mediated toxicity. We recently reported that E14 rat fetal mesencephalon could be efficiently tranduced by adeno-associated virus type 2 (AAV2) vectors and that gene expression was maintained until at least 3 months after transplantation in the adult rat striatum. Here we report that an AAV2 vector can mediate the expression of the EGFP reporter gene under the control of a CMV promoter in organotypic cultures of freshly explanted solid fragments of human fetal mesencephalic tissue as early as 3 days to at least 6 weeks postinfection. These results suggest that AAV2 vectors could be used to genetically modify the human fetal tissue prior to transplantation to Parkinson’s patients to promote graft survival and integration.
Document Type: Research Article
Affiliations: 1: *Laboratory of Experimental Neurosurgery, †Department of Neurosurgery, Hôpital Erasme, ULB, Belgium 2: ¶INSERM U421, Hôpital Mondor, Créteil, France 3: ‡Department of Gynecology, Hôpital Erasme, ULB, Belgium 4: §Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, ULB, Belgium
Publication date: January 1, 2004
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