Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation.
Blood. 1994 May 1;83(9):2737-48. Unique Identifier : AIDSLINE MED/94220722 Krall WJ; Challita PM; Perlmutter LS; Skelton DC; Kohn DB; Division of Research Immunology and Bone Marrow Transplantation,; Childrens Hospital, Los Angeles, CA 90027.
Abstract:
Gaucher disease is an inherited lysosomal storage disease in which the loss in functional activity of glucocerebrosidase (GC) results in the storage of its lipid substrate in cells of the macrophage lineage. A gene therapy approach involving retroviral transduction of autologous bone marrow (BM) followed by transplantation has been recently approved for clinical trial. Amelioration of the disease symptoms may depend on the replacement of diseased macrophages with incoming cells expressing human GC; however, the processes of donor cell engraftment and vector gene expression have not been addressed at the cellular level in relevant tissues. Therefore, we undertook a comprehensive immunohistologic study of macrophage and microglia replacement after murine BM transplantation with retrovirus-marked BM. Serial quantitative PCR analyses were employed to provide an overview of the time course of engraftment of vector-marked cells in a panel of tissues. Following reconstitution of hematopoietic tissues with vector-marked donor cells at early stages, GC+ cells began to infiltrate the liver, lung, brain, and spinal cord by 3 months after transplant. Immunohistochemical analyses of PCR+ tissues using the 8E4 monoclonal antibody specific for human GC revealed that macrophages expressing human GC had partially reconstituted the Mac-1+ population in all tissues in a manner characteristic to each tissue type. In the brain, 20% of the total microglia had been replaced with donor cells expressing GC by 3 to 4 months after transplant. The finding that significant numbers of donor cells expressing a retroviral gene product immigrate to the central nervous system suggests that gene therapy for neuronopathic forms of lysosomal storage diseases as well as antiviral gene therapy for AIDS may be feasible.
Keywords: Animal *Bone Marrow Transplantation Brain/CYTOLOGY *Gene Expression Genetic Markers Genetic Vectors Glucosylceramidase/*GENETICS Human Immunohistochemistry Macrophages/*CYTOLOGY/ENZYMOLOGY Male Mice Mice, Inbred C57BL Microglia/*CYTOLOGY/ENZYMOLOGY Polymerase Chain Reaction Retroviridae/*GENETICS Spleen/CYTOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. JOURNAL ARTICLE 940830
M9480756
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
