Thymulin gene therapy in animal models of thymus deficiency

GOYA RODOLFO G

Rio de Janeiro

Congreso; VII Congress of the International Society of Neuroimmunomodulation; 2008

International Society for Neuroimmunomodulation

Thymulin gene therapy in animal models of thymus deficiency Goya RG INIBIOLP,  University of La Plata, Argentina Introduction: Thymulin (FTS-Zn) is a bioactive thymic peptide involved in several aspects of intra and extrathymic T-cell differentiation. In the brain, thymulin possesses antiinflammatory activity and acts as a hypophysotropic molecule. Methodology: We constructed a synthetic DNA sequence, 5’-ATGCAAGCCAAATCTCAAGGTGGATCCAACTAGTAG-3’, encoding met-FTS, a biologically active analog of thymulin, and subsequently cloned it into different expression vectors. The met-FTS DNA sequence was cloned in the mammalian expression vector phMGFP (which expresses the Monster Green Fluorescent Protein), thus obtaining p-metFTS-hMGFP, which expresses the fluorescent fusion protein metFTS-hMGFP. We also cloned the  met-FTS DNA sequence in a recombinant adenoviral (RAd) vector, termed RAd-metFTS.  Results: RAd-metFTS was injected intramuscularly in thymectomized (Tx) and nude mice as well as in Tx rats. Transduced myocytes acted as an ectopic source of thymulin thus restoring circulating thymulin levels to normal values. This restorative effect was long lasting (several months). In the rat brain, adenovirally-mediated delivery of the synthetic gene for thymulin achieved longer expression than in the case of adenovirally-delivered reporter genes, which is consistent with the reported antiinflammatory activity of thymulin in the brain. Furthermore, neonatal thymulin gene therapy in nude female mice was able to prevent the pituitary and ovarian alterations that typically occur in this mutant after puberty. Conclusions: The availability of the above biotechnological  tools should boost basic studies on the molecular biology of thymulin and also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models and eventually, in humans.  Support: ANCYPT-CONICET-INSERM-NIH