A Novel Homologous Model for Gene Therapy of Dwarfism by Non-Viral Transfer of the Mouse Growth Hormone Gene into Immunocompetent Dwarf Mice
Claudia R. Cecchi,
Nelio A.J. Oliveira,
Eliana R. Lima,
Thomas G. Jensen,
Alexander A.L. Jorge,
Cibele N. Peroni.
The possibilities for non-viral GH gene therapy are studied in immunocompetent dwarf mice (lit/lit). As expression
vector we used a plasmid previously employed in immunodeficient dwarf mice (pUBI-hGH-gDNA) by replacing
the human GH gene with the genomic sequence of mouse-GH DNA (pUBI-mGH-gDNA). HEK-293 human cells transfected
with pUBI-mGH-gDNA produced 3.0 µg mGH/106 cells/day compared to 3.7 µg hGH/106 cells/day for pUBIhGH-
gDNA transfected cells. The weight of lit/lit mice treated with the same two plasmids (50 µg DNA/mouse) by electrotransfer
into the quadriceps muscle was followed for 3 months. The weight increase up to 15 days for mGH, hGH and
saline treated mice were 0.130, 0.112 and 0.027 g/mouse/day. Most sera from hGH-treated mice contained anti-hGH antibodies
already on day 15, with the highest titers on day 45, while no significant anti-mGH antibodies were observed in
mGH-treated mice. At the end of 3 months, the weight increase for mGH-treated mice was 34.3%, while the nose-to-tail
and femur lengths increased 9.5% and 24.3%. Mouse-GH and hGH circulating levels were 4-5 ng/mL 15 days after treatment,
versus control levels of ~0.7 ng GH/mL (P<0.001). In mGH-treated mice, mIGF-I determined on days 15, 45 and
94 were 1.5- to 3-fold higher than the control and 1.2- to 1.6-fold higher than hGH-treated mice. The described homologous
model represents an important progress forming the basis for preclinical testing of non-viral gene therapy for GH deficiency.
Keywords: Gene therapy, homologous model, IGF-I, little mice, mouse growth hormone, non-viral gene transfer.
Rights & PermissionsPrintExport