       Document 0149
 DOCN  M9460149
 TI    Cells expressing human glucocerebrosidase from a retroviral vector
       repopulate macrophages and central nervous system microglia after murine
       bone marrow transplantation.
 DT    9408
 AU    Krall WJ; Challita PM; Perlmutter LS; Skelton DC; Kohn DB; Division of
       Research Immunology and Bone Marrow Transplantation,; Childrens
       Hospital, Los Angeles, CA 90027.
 SO    Blood. 1994 May 1;83(9):2737-48. Unique Identifier : AIDSLINE
       MED/94220722
 AB    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.
 DE    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

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

