title: Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation.
abstract: Previous clinical attempts to correct genetic deficiencies such as hemophilia or Gaucher disease by transplantation of allogeneic spleen were associated with aggressive graft versus host disease, mediated by mature T cells derived from the donor spleen. We show that a fetal pig spleen harvested at the embryonic day 42 stage, before the appearance of T cells, exhibited optimal growth potential upon transplantation into SCID mice, and the growing tissue expressed factor VIII. Transplantation of embryonic day 42 spleen tissue into hemophilic SCID mice led to complete alleviation of hemophilia within 2-3 months after transplant, as demonstrated by tail bleeding and by assays for factor VIII blood levels. These results provide a proof of principle to the concept that transplantation of a fetal spleen, obtained from a developmental stage before the appearance of T cells, could provide a novel treatment modality for genetic deficiencies of an enzyme or a factor that can be replaced by the growing spleen tissue.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Aronovich
authors.forename: Dalit
authors.initials: D
authors.lastname: Tchorsh
authors.forename: Helena
authors.initials: H
authors.lastname: Katchman
authors.forename: Smadar
authors.initials: S
authors.lastname: Eventov-Friedman
authors.forename: Elias
authors.initials: E
authors.lastname: Shezen
authors.forename: Uri
authors.initials: U
authors.lastname: Martinowitz
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Sivan
authors.initials: S
authors.lastname: Cohen
authors.forename: Orna
authors.initials: O
authors.lastname: Tal
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000818:Animals; D015415:Biomarkers; D004194:Disease; D004622:Embryo, Mammalian / Q000601:surgery; D005169:Factor VIII / Q000378:metabolism; D006085:Graft Survival / Q000276:immunology; D006467:Hemophilia A / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D013552:Swine; D016378:Tissue Transplantation / Q000009:adverse effects*; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; D005169:Factor VIII