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Synthetic biology, optimized codons and microRNAs for replacement therapy for patients with Gaucher disease

Grant number: 13/50764-7
Support Opportunities:Regular Research Grants
Duration: January 01, 2014 - February 29, 2016
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Convênio/Acordo: MIT
Principal Investigator:Aparecida Maria Fontes
Grantee:Aparecida Maria Fontes
Principal researcher abroad: Ron Weiss
Institution abroad: Massachusetts Institute of Technology (MIT), United States
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:11/20829-4 - Epigenetic mechanisms of HOX gene modulation in medulloblastoma, AP.R


This proposal has two components: the research and educational. The research component focus on Gaucher disease, Gaucher disease is an autosomal recessive disease with a prevalence of 1:60,000 to 1:200,000 births. So far there is no cure, but there is treatment. Current treatments consist of replacement therapy with placenta-derived glucocerebrosidase (pdGBA) or recombinant glucocerebrosidase (rGBA). Despite the advantages of rGBA compared to pdGBA, such as reduced risks of viral contamination, the recombinant product is expensive, a fact that impairs adequate treatment. One innovation consists on the generation of a biopharmaceutical by synthetic biology, which facilitates the design of a complex DNA vector to support high level production of the therapeutic protein. Therefore, the main objective of this proposal is to develop four lentiviral expression vectors for GBA production in human cell lines using synthetic biology approaches together with MIT group. After the development of these synthetic lentiviral expression vectors it will be performed in vitro assays in order to answer three main questions: 1) to investigate whether or not these synthetic lentiviral vectors are stable, which means they are able to produce virions after infection into 293T human cell line; 2) to investigate the functionality of these synthetic vectors, which means it will allow the transient expression of two synthetic cDNAS GBA and puromycin after three cycles of transduction of these virions into the same human cell line and 3) to evaluate the functionality of these both synthetic proteins by in vitro assays. This proposal is part of a research project which involve the generation of four human cell lines with stable production of GBA for replacement therapy to Gaucher disease. We propose three stages for this partnership: 1) FMRP-USP group will design the four lentiviral vectors containing two synthetic cDNAs - GBA and puromycin; 2) MIT group will synthesize these four vectors and 3) FMRP-USP group will evaluated the functionality of these vectors and the two synthetic proteins using in vitro assays to evaluate the biological activity of these proteins. The execution of this research component will lead to the development of a fourth-generation synthetic biopharmaceuticai for replacement therapy for Gaucher disease. The educational component focuses on BioBuilder program from MIT with the interest to expand for Ribeirão Preto high schools along with USP students who will be trained as BioBuilder teachers. The MIT-BioBuilder program presents current challenges in the field of synthetic biology as teachable classroom modules that fit squarely into formal education settings, empowering students as young as 12 years old to tackle big questions. BioBuilder converts students, teachers and amateurs into scientists, working at the edge of what's known and problem solving to address the world's issues. There are three aspects to BioBuilder model for education: 1) online animations that present concepts and challenges in the field; 2) classroom lessons and laboratory activities for teachers and students to perform data analysis and discussion portals for participants to share what they've learned and 3) to provide teacher-training workshops throughout the year such as webinars and virtual conferences. We propose three stages for this partnership: 1) BioBuilder Educational Foundation will train two USP students offering a teacher-training workshop; 2) two USP students will translate into Portuguese the material from BioBuilder Educational program. To perform that it will be required ongoing virtual meetings and 3) a group of four USP students will recruit high school students and will teach a course with main content about synthetic biology concepts. The execution of this educational component will lead to develop a synthetic biology course for students of high schools from Ribeirão Preto. (AU)

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