Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/34583
Title: INTRAUTERINE GENE THERAPY IN A NON-HUMAN PRIMATE MODEL
Authors: CITRA NURFARAH BINTE ZAINI MATTAR
Keywords: intrauterine, fetal, gene therapy, non-human primate, vector, therapeutic effect, adverse outcomes
Issue Date: 10-Jan-2012
Source: CITRA NURFARAH BINTE ZAINI MATTAR (2012-01-10). INTRAUTERINE GENE THERAPY IN A NON-HUMAN PRIMATE MODEL. ScholarBank@NUS Repository.
Abstract: Intrauterine gene therapy (IUGT) is designed to treat monogenic diseases in the early stages of pathogenesis, targeting the disorders that cause severe perinatal morbidity or mortality. I investigated the hypothesis that the non-human primate (NHP) is a relevant model in which to validate clinically-relevant IUGT strategies. Non-integrating adeno-associated vectors (AAV) were used for specific organ-targeting approaches with clinically-relevant vector-delivery techniques and outcomes were monitored. Liver-targeting late-gestation IUGT (at 0.9G) with AAV8- or AAV5-hFIX resulted in long-term therapeutic transgene expression with widespread vector biodistribution despite a capsid-directed humoral response. Random vector integration occurred with no evidence of tumourigenesis. Comparatively, early-IUGT (0.4G) with the same vectors resulted in lower dose-dependent expression and a transient humoral response. Late-IUGT using AAV9-eGFP displayed robust expression in all organs, particularly throughout the CNS. Neurons, oligodendrocytes and retinal cells were efficiently transduced. Thus, a robust NHP model of IUGT provides clinically-relevant data, and future research must focus on validating individual strategies for selected fetal diseases.
URI: http://scholarbank.nus.edu.sg/handle/10635/34583
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