Gene therapy for alpha 1-antitrypsin deficiency. 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 and characterised by very reduced serum levels of the anti-protease. Alpha 1 antitrypsin is primarily produced in the liver by hepatocytes and then passes into the general circulation to diffuse into the pulmonary tissue. Its function is to inhibit the elastase secreted by the polymorpho-nuclear neutrophils. When the quantity of alpha 1 antitrypsin secreted into the circulation is insufficient to inhibit the elastase, the pulmonary tissue is progressively destroyed leading to the appearance 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 restore a sufficient level of alpha 1 antitrypsin to inactivate the elastase in the pulmonary tissue and thus prevent the appearance of emphysema. Mumerous experimental protocols have been developed in vivo in animals since 1987. They identify the two principal current difficulties for the development of clinical trials: the brevity of the duration of expression of the transferred gene which does not last more than a few months, and insufficient levels of alpha 1 antitrypsin which are obtained usually less than the therapeutic level required.