title: Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC.
abstract: We recently re-established a line of sheep that accurately mimics the clinical symptoms and genetics of severe hemophilia A (HA). Here, we tested a novel, nonablative transplantation therapy in two pediatric HA animals. Paternal mesenchymal stem cells (MSC) were transduced with a porcine FVIII-encoding lentivector and transplanted via the intraperitoneal route without preconditioning. At the time of transplantation, these animals had received multiple human FVIII treatments for various spontaneous bleeds and had developed debilitating hemarthroses, which produced severe defects in posture and gait. Transplantation of transduced MSC resolved all existent hemarthroses, and spontaneous bleeds ceased. Damaged joints recovered fully; the animals regained normal posture and gait and resumed normal activity. Despite achieving factor-independence, a sharp rise in pre-existent Bethesda titers occurred following transplantation, decreasing the effectiveness and duration of therapy. Postmortem examination revealed widespread engraftment, with MSC present within the lung, liver, intestine, and thymus, but particularly within joints affected at the time of transplantation, suggesting MSC homed to sites of ongoing injury/inflammation to release FVIII, explaining the dramatic improvement in hemarthrotic joints. In summary, this novel, nonablative MSC transplantation was straightforward, safe, and converted life-threatening, debilitating HA to a moderate phenotype in a large animal model.
authors: Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC., USA. cporada@wfubmc.edu
authors: Christopher D
authors: CD
authors: Porada
authors: Chad
authors: C
authors: Sanada
authors: Chung-Jung
authors: CJ
authors: Kuo
authors: Evan
authors: E
authors: Colletti
authors: Walter
authors: W
authors: Mandeville
authors: John
authors: J
authors: Hasenau
authors: Esmail D
authors: ED
authors: Zanjani
authors: Robert
authors: R
authors: Moot
authors: Christopher
authors: C
authors: Doering
authors: H Trent
authors: HT
authors: Spencer
authors: Graça
authors: G
authors: Almeida-Porada
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002465:Cell Movement; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival; D006395:Hemarthrosis / Q000209:etiology / Q000473:pathology; D006467:Hemophilia A / Q000150:complications / Q000188:drug therapy / Q000601:surgery*; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D007274:Injections, Intraperitoneal; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000821:virology; D010641:Phenotype; D011994:Recombinant Proteins / Q000627:therapeutic use; D012074:Remission Induction; D012756:Sheep / Q000097:blood / Q000235:genetics*; D034421:Sus scrofa / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D007518:Isoantibodies; D011994:Recombinant Proteins; D005169:Factor VIII