Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation.
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.
Aronovich
Anna
A
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Tchorsh
Dalit
D
Katchman
Helena
H
Eventov-Friedman
Smadar
S
Shezen
Elias
E
Martinowitz
Uri
U
Blazar
Bruce R
BR
Cohen
Sivan
S
Tal
Orna
O
Reisner
Yair
Y
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
D015415:Biomarkers; D005169:Factor VIII