Murine MHC class II locus control region drives expression of human beta-glucocerebrosidase in antigen presenting cells of transgenic mice

Gaucher disease is the most prevalent lysosomal storage disorder in humans, resulting from an inherited deficiency, of the enzyme glucocerebrosidase. Although the enzyme is ubiquitously expressed, cells of the reticuloendothe lial system are particularly affected since they accumulate the undigested glucosylceramide substrate through their role in scavenging and breaking do wn cell debris. Gaucher disease is an attractive target for somatic gene th erapy. To test the ability to express the enzyme in the affected cell types we have generated transgenic mice expressing human glucocerebrosidase unde r the control of the murine major histocompatibility complex (MHC) class II Ea(d) locus control region (LCR). The four transgenic lines express the hu man enzyme in a copy number-dependent manner, independent of the integratio n site of the transgene. Overexpression of the human enzyme in mice did not result in any abnormal phenotype or pathology during the period of observa tion (> 2 years). The enzyme is expressed in B cells. monocytes, dendritic cells thymic epithelial cells, and macrophages in various tissues: the peri toneal cavity, bone marrow, spleen, kidney, gastrointestinal tract, Kupffer cells in the liver and alveolar macrophages in lungs. Expression in the br ain was limited to perivascular macrophages and was not seen in microglial cells. Therefore, the MHC class II LCB could potentially be of use in somat ic gene therapy for type I Gaucher disease.