RESUMO
Despite long-standing efforts to enhance care for chronic asthma, symptomatic treatments remain the only option to manage this highly prevalent and debilitating disease. We demonstrate that key pathology of allergic asthma can be almost completely resolved in a therapeutic manner by inhaled gene therapy. After the disease was fully and stably established, we treated mice intratracheally with a single dose of thymulin-expressing plasmids delivered via nanoparticles engineered to have a unique ability to penetrate the airway mucus barrier. Twenty days after the treatment, we found that all key pathologic features found in the asthmatic lung, including chronic inflammation, pulmonary fibrosis, and mechanical dysregulation, were normalized. We conducted tissue- and cell-based analyses to confirm that the therapeutic intervention was mediated comprehensively by anti-inflammatory and antifibrotic effects of the therapy. We believe that our findings open a new avenue for clinical development of therapeutically effective gene therapy for chronic asthma.
Assuntos
Asma , Nanopartículas , Animais , Asma/genética , Asma/terapia , Modelos Animais de Doenças , Terapia Genética , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/uso terapêutico , Fator Tímico Circulante/genética , Fator Tímico Circulante/farmacologia , Fator Tímico Circulante/uso terapêuticoRESUMO
Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to the molecule. After its discovery in the early 1970s, thymulin was characterized as a thymic hormone involved in several aspects of intrathymic and extrathymic T cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to thymulin as a hypophysotropic peptide. In recent years, interest has arisen in the potential use of thymulin as a therapeutic agent. Thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. Furthermore, an adenoviral vector harboring a synthetic gene for thymulin, stereotaxically injected in the rat brain, achieved a much longer expression than the adenovirally mediated expression in the brain of other genes, thus suggesting that an anti-inflammatory activity of thymulin prevents the immune system from destroying virus-transduced brain cells. Other studies suggest that thymulin gene therapy may also be a suitable therapeutic strategy to prevent some of the endocrine and metabolic alterations that typically appear in thymus-deficient animal models. The present article briefly reviews the literature on the physiology, molecular biology, and therapeutic potential of thymulin.
Assuntos
Terapia Genética , Sistemas Neurossecretores/fisiologia , Peptídeos/genética , Peptídeos/uso terapêutico , Fator Tímico Circulante/genética , Fator Tímico Circulante/uso terapêutico , Timo/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Homeostase , Humanos , Dados de Sequência Molecular , Peptídeos/química , Fator Tímico Circulante/biossíntese , Fator Tímico Circulante/químicaRESUMO
Thymulin is a pharmacologically active metallononapeptide inducing the differentiation of T cells and enhancing several functions of the various T cell subsets in normal or partially thymus-deficient recipients. Its effect on suppressor T cells is, so far, the most remarkable and should be the first to find useful clinical applications. The peptide is a natural hormone, available in synthetic form. It is not toxic and one may foresee its clinical use as one of the major immunoregulatory agents in the near future.