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Platform for the development of a human cell line with a high number copies of the synthetic b-glucocerebrosidase cDNA with optimized codons for Gaucher disease

Grant number: 14/15846-5
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2014
Effective date (End): July 09, 2018
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Aparecida Maria Fontes
Grantee:Ana Carolina Coelho
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Gaucher disease is characterized as an autosomal recessive disorder caused by mutations in the enzyme ²-glucocerebrosidase (GBA) gene. This disease has no cure, only treatment. One of the current treatment consists of replacement therapy via intravenous infusions of GBA placenta-derived (pGBA) or recombinant GBA (rGBa). Despite the advantages of rGBA compared to pGBA, such as reducing the risk of viral contamination, the access to the recombinant enzyme is limited due to its high cost and in availability. An emerging field in science is synthetic biology, which can accelerate the development of new biopharmaceutical products and be more cost-efficient. Obtaining the first prokaryotic organism by synthetic biology has led us to the hypothesis that it could be used to obtain the functional GBA. Therefore, the objective of this project is to develop an optimized platform for obtaining a human cell line with stable production of synthetic GBA and carrier preferred codons. To make that, human cell line will be submitted to multiple rounds of transduction with a third generation of lentiviral vector carrying the synthetic GBA cDNA and synthetic puromycin cDNA. In the first, fifth and tenth cycle of transduction, the transduced cells will be characterized as: the number of copies of the GBA cDNA in the cell genome; the mRNA level and level of GBA protein. At the end of the cycles of transduction, cells will be treated with puromycin to select a cell clone with high levels of GBA protein. This project will lead to the development of a biopharmaceutical, as well as a platform optimized for obtaining a cell line with high productivity of GBA for replacement therapy of individuals with Gaucher disease. This project includes some of the objectives from two research projects recently approved by FAPESP: Proc. Numbers: 2013/50450-2 (AP.PITE 1) e 2013/50764-7 (AP.R). (AU)

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