Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical

Author(s)

Higuti, Eliza ^[1] ; Cecchi, Claudia R. ^{[1, 2]} ; Oliveira, Nelio A. J. ^{[1, 3]} ; Lima, Eliana R. ^[1] ; Vieira, Daniel P. ^[1] ; Aagaard, Lars ^[2] ; Jensen, Thomas G. ^[2] ; Jorge, Alexander A. L. ^[4] ; Bartolini, Paolo ^[1] ; Peroni, Cibele N. ^[1]

Affiliation

^[1] CNEN, IPEN, Ctr Biotechnol, Cidade Univ, Ave Prof Lineu Prestes 2242, BR-05508900 Sao Paulo, SP - Brazil

^[2] Aarhus Univ, Dept Biomed, DK-8000 Aarhus - Denmark

^[3] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN - USA

^[4] Univ Sao Paulo, Sch Med, FMUSP, Genet Endocrinol Unit LIM25, Endocrinol Dept, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: GROWTH HORMONE & IGF RESEARCH; v. 26, p. 1-7, FEB 2016.
• Web of Science Citations: 2

Abstract

Non-viral transfer of the growth hormone gene to different muscles of immunodeficient dwarf (lit/scid) mice is under study with the objective of improving phenotypic correction via this particular gene therapy approach. Plasmid DNA was administered into the exposed quadriceps or non-exposed tibialis cranialis muscle of lit/scid mice followed by electroporation, monitoring several growth parameters. In a 6-month bioassay, 50 pg DNA were injected three times into the quadriceps muscle of 80-day old mice. A 50% weight increase, with a catch-up growth of 21%, together with a 16% increase for nose-to-tail and tail lengths (catch-up = 19-21%) and a 24-28% increase for femur length (catch-up = 53-60%), were obtained. mIGF1 serum levels were similar to 7-fold higher than the basal levels for untreated mice, but still similar to 2-fold lower than in non-dwarf scid mice. Since treatment age was found to be particularly important in a second bioassay utilizing 40-day old mice, these pubertal mice were compared in a third bioassay with adult (80-day old) mice, all treated twice with 50 mu g DNA injected into each tibialis cranialis muscle, via a less invasive approach. mIGF1 concentrations at the same level as co-aged scid mice were obtained 15 days after administration in pubertal mice. Catch-up growth, based on femur length (77%), nose-to-tail (36%) and tail length (39%) increases was 40 to 95% higher than those obtained upon treating adult mice. These data pave the way for the development of more effective pre-clinical assays in pubertal dwarf mice for the treatment of GH deficiency via plasmid-DNA muscular administration. (C) 2015 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 14/04277-0 - Growth Hormone Gene therapy: homologous treatment based on plasmid DNA administration and on microencapsulated cells implanted in immunocompetent dwarf mice (lit/lit)
• Grantee: Claudia Regina Cecchi
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 14/18242-3 - Gene therapy for growth hormone deficiency mediated by minicircle DNA electrotransfer in dwarf mice
• Grantee: Eliza Higuti Sousa
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/03747-0 - Growth hormone gene therapy: homologous treatment with plasmid DNA and with implant of microencapsulated cells in immunocompetent dwarf mice (lit/lit)
• Grantee: Claudia Regina Cecchi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/21708-6 - Complete phenotypic correction of dwarfism by injection of plasmid DNA in an animal model of isolated growth hormone deficiency
• Grantee: Eliza Higuti Sousa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/19757-7 - Growth hormone gene therapy: plasmid DNA injection and microencapsulated cells implantation in dwarf mice
• Grantee: Cibele Nunes Peroni
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/07380-6 - Optimization of in vivo growth hormone gene transfer parameters for phenotypic correction of dwarf mice
• Grantee: Eliana Rosa Lima Filha
• Support Opportunities: Scholarships in Brazil - Master