Approach to gene therapy of glycogenosis type II (Pompe disease).

Pompe disease is a generalized lysosomal glycogenosis affecting essentially the skeletal muscles and the heart. It is due to the deficiency of acid alpha-glucosidase, also called acid maltase, involved in glycogen degradation by the cleavage of alpha-1,4 and alpha-1,6 glycosidic linkages. The severe infantile, milder juvenile, and late-onset or adult forms are associated under the generic name of glycogenoses type II. The clinical picture can differ according to these variants, forming a clinical spectrum from cardiorespiratory failure with early death in the infantile variant to late muscular weakness or respiratory problems in the adult variant. Enzymatic pre- and postnatal diagnoses and mutation characterization are available. Different therapeutic attempts have been conceived and some of them have come to clinical trials. Several pilot studies have demonstrated the feasibility of gene therapy and remarkable advances have been realized. Of particular interest, strategies for gene therapy in a generalized disease like Pompe disease must be accompanied by the secretion and uptake of the corrective enzyme by more distant cells or tissues in order to obtain efficient results. Preliminary positive results have been obtained in animal models, and new approaches with improvements in the access to muscle and heart, in the efficacy and innocuity of vectors, and in the clinical evolution are proposed. Gene therapy is a promising strategy for Pompe disease. However, several steps must be explored before this method becomes clinically successful.