Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by defects in the acid a-glucosidase gene (GAA), which leads to lysosomal glycogen accumulation and enlargement of the lysosomes mainly in cardiac and muscle tissues, resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severely affected patients. Enzyme replacement therapy (ERT) has already proven to be beneficial in this disease, but correction of pathology in skeletal muscle still remains a challenge. Furthermore, the production of antibodies following ERT can limit the treatment efficacy as severe adverse effects can accompany the immune response. In this study, Dr. Douillard-Guilloux and colleagues report for the first time, the use of hematopoietic stem cell (HSC) gene therapy as a potentially curative treatment for GSDII in a murine model of the disease. Transplantation of lentivirally transduced GAA-deficient HSC into lethally irradiated GSDII mice leads to an efficient bone marrow engraftment. Human GAA expression in HSC generated a significant increase of enzymatic activity both bone marrow cells and mature hematopoietic cells. GAA activity was associated with a substantial clearance of lysosomal glycogen storage, especially in skeletal muscle and liver. Moreover, in the absence of transgene immunization, GAA-transplanted mice did not develop any immune reaction against the transgene product, suggesting tolerance induction. The data from this study is very promising and indicate that that HSC gene therapy can be used in association with ERT to improve the therapeutic efficacy in Pompe disease.
This work was supported by the AFM.

Références : J Gene Med. 2009 Apr;11(4):279-87.