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Growth hormone gene therapy: plasmid DNA injection and microencapsulated cells implantation in dwarf mice

Grant number: 14/19757-7
Support type:Regular Research Grants
Duration: March 01, 2015 - February 28, 2017
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Cibele Nunes Peroni
Grantee:Cibele Nunes Peroni
Home Institution: Instituto de Pesquisas Energéticas e Nucleares (IPEN). Secretaria de Desenvolvimento Econômico (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Paolo Bartolini


In previous works we have developed alternative methodologies for ex vivo and in vivo gene therapy directed to the phenotypic correction of dwarfism using the human (hGH) and mouse growth hormone (mGH) genes. In these studies two animal models of GH deficiency, the immunocompetent dwarf (lit/lit) and the immunodeficient dwarf (lit/scid) mice, were employed. Both in the ex vivo, based on implant of human keratinocytes transduced with retroviral vectors, as well as in the in vivo methodology, based on the electrotransfer of plasmid DNA in the quadriceps muscle of mice, significant phenotypic effects were obtained with body weight increase of up to ~ 50 %, corresponding to an approximation to normalization (catch-up growth) of 27% compared to the normal size mouse, especially in the case of in vivo methodology. In the present project, with the goal of increasing this percentage of phenotypic correction and move closer to pre-clinical testing, we plan: A) to give continuity to researches related to our model of in vivo gene therapy introducing alternative administrations of mGH or hGH plasmid DNA in lit/lit or lit/scid mice; B) to implant microencapsulated human retinal epithelial cells, transfected by a transposon system and expressing hGH or mGH in lit/lit mice. In the first activity we will study the possibilities of using the plasmidic vectors in less aggressive protocols of electrotransfer without muscle exposition and selection of another muscle, e.g. the tibialis cranialis or use of an attenuated hydrodynamic injection (pseudo-hydrodynamic) and younger mice (< 40 days of age), evaluating the conditions that allow higher levels of circulating IGF-I, in analogy with the treatment conditions of GH-deficient children. In the second case we will develop an alternative technique, in which human epithelial cells already successfully applied in clinical protocols of cell therapy will be used, for the first time, in a model for the treatment of GH deficiency. (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)
CECCHI, C. R.; HIGUTI, E.; LIMA, E. R.; VIEIRA, D. P.; SQUAIR, P. L.; PERONI, C. N.; BARTOLINI, P. Efficient Non-Invasive Plasmid-DNA Administration into Tibialis Cranialis Muscle of ``Little{''} Mice. CURRENT MOLECULAR MEDICINE, v. 17, n. 3, p. 230-235, 2017. Web of Science Citations: 0.
HIGUTI, ELIZA; CECCHI, CLAUDIA R.; OLIVEIRA, NELIO A. J.; LIMA, ELIANA R.; VIEIRA, DANIEL P.; AAGAARD, LARS; JENSEN, THOMAS G.; JORGE, ALEXANDER A. L.; BARTOLINI, PAOLO; PERONI, CIBELE N. Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical. GROWTH HORMONE & IGF RESEARCH, v. 26, p. 1-7, FEB 2016. Web of Science Citations: 2.

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