1. ¹Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA
2. ²Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Avenue, St. Louis, MO 63104, USA

Correspondence: Mark S. Sands, Fax: (314) 362-9333. E-mail: msands@im.wustl.edu

Received 23 December 2003; Accepted 15 March 2004.

Abstract

As a group, lysosomal storage diseases (LSDs) affect roughly 1 in 6700 live births. Treatment of patients with enzyme replacement therapy or allogeneic bone marrow transplantation is severely limited by cost and clinical complications, respectively. In this study, the efficacy of gene therapy targeted to human hematopoietic progenitor cells was investigated for mucopolysaccharidosis type VII (MPSVII), a LSD caused by -glucuronidase (GUSB) deficiency. Clinical experience has emphasized the need to evaluate transduction protocols directly with human cells through in vivo assays. Therefore, GUSB-deficient mobilized peripheral blood CD34⁺ cells from a patient with MPSVII were transduced with a third-generation lentiviral vector encoding human GUSB and then assessed in a xenotransplantation system. In this novel strategy, the xenotransplanted murine recipients were also GUSB-deficient, allowing a detailed evaluation of therapeutic efficacy in a host with MPSVII. Twelve weeks posttransplantation, lymphomyeloid expression of GUSB was detected in 10.8 1.6% of the human cells in the bone marrow with an average of 1 to 2 vector genomes measured per positive cell. The corrected cells distributed widely throughout recipient tissues, resulting in significant therapeutic effects including improvements in biochemical parameters and reduction of the lysosomal distension of several host tissues.