Evaluation of the safety profile related to the use of retroviral and lentiviral vectors for gene therapy in the hematopoietic system

• Grant number: 09/51386-0
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2010
• End date: August 31, 2012
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Bryan Eric Strauss
• Grantee: Bryan Eric Strauss
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Retroviral vectors (and in particular, those derived from the Moloney Murine Leukemia Virus, MoMLV) are among the principle vectors utilized in gene therapy clinical trials, including the treatment of hematopoietic diseases such as Xl-SCID. Though the treatment of this disease was quite successful, some patients presented leukemia that was attributed to clonal proliferation that resulted from a combination of factors, including retroviral insertional mutagenesis, a possible proliferative advantage conferred by the therapeutic gene as well as the phenotype of the cells being treated. In recent years, vectors derived from lentivirus have been developed for clinical application and offer the advantage that these vectors are capable of transducing postmitotic cells and present an integration profile that appears to be safer than MoMLV. However, the vector's impact on the rise of adverse events, such as clonal expansion, is difficult to measure quantitatively. In this project, we plan to develop a new method which will permit the observation, in a simple and rapid manner, of the clonality of cell populations transduced with retroviral and lentiviral vectors. Once the new method has been validated, we plan to employ it for the evaluation of the influence of the viral promoter and therapeutic gene contained in the retroviral and lentiviral vector on the tendency towards clonal expansion in a model of Xl-SCID. This technology could also be utilized to monitor the populational clonality when different cell types (lineage-negative stem cells, Side Population cells) are transduced under a variety of conditions (cytokine activation, duration of activation). (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZANATTA, DANIELA B.; TSUJITA, MARISTELA; BORELLI, PRIMAVERA; AGUIAR, RODRIGO B.; FERRARI, DANIEL G.; STRAUSS, BRYAN E.. Genetic barcode sequencing for screening altered population dynamics of hematopoietic stem cells transduced with lentivirus. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, v. 1, 2014. (09/51386-0, 13/25167-5, 14/03205-5)

Filed patent(s) as a result of this research project