GENE-THERAPY FOR ALPHA-1-ANTITRYPSIN DEFI CIENCY - HOPES, REALITIES AND PERSPECTIVES

Alpha 1 antitrypsin deficiency (alpha 1 AT) is an autosomal recessive disease due to mutations in the gene coding for alpha 1 antitrypsin an d characterised by very reduced serum levels of the anti-protease. Alp ha 1 antitrypsin is primarily produced in the liver by hepatocytes and then passes into the general circu lation to diffuse into the pulmona ry tissue. Its function is to inhibit the elastase secreted by the pol ymorpho-nuclear neutrophils. When the quantity of alpha 1 antitrypsin secreted into the circulation is insufficient to inhibit tile elastase , the pulmonary tissue is progressively destroyed leading to the appea rance of emphysema around 30 to 40 years of age. Gene therapy in alpha 1 antitrypsin deficiency rests on the transfer and the expression of a copy of the normal human alpha 1 antitrypsin gene by the cells of an organism of a subject suffering from the disease. The aim is to resto re a sufficient level of alpha 1 antitrypsin to inactivate the elastas e in the pulmonary tissue and thus prevent the appearance of emphysema . Mumerous experimental protocols have been developed in vivo in anima ls since 1987. They identify the two principal current difficulties fo r the development of clinical trials: the brevity of the duration of e xpression of the transferred gene which does not last more than a few months, and insufficient levels of alpha 1 antitrypsin which are obtai ned usually less than the therapeutic level required.