In Utero Transplantation of Placenta-Derived Mesenchymal Stromal Cells for Potential Fetal Treatment of Hemophilia A

Priyadarsini Kumar, Kewa Gao, Chuwang Wang, Christopher Pivetti, Lee Lankford, Diana L Farmer, Aijun Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the factor VIII (FVIII) gene leading to deficient blood coagulation. The current standard of care is frequent infusions of plasma-derived FVIII or recombinant B-domain-deleted FVIII (BDD-FVIII). While this treatment is effective, many patients eventually develop FVIII inhibitors that limit the effectiveness of the infused FVIII. As a monogenic disorder, HA is an ideal target for gene or cell-based therapy. Several studies have investigated allogeneic stem cell therapy targeting in utero or postnatal treatment of HA but have not been successful in completely correcting HA. Autologous in utero transplantation of mesenchymal stem cells is promising for treatment of HA due to the naive immune status of the fetal environment as well as its potential to prevent transplant rejection and long-term FVIII inhibitor formation. HA can be diagnosed by chorionic villus sampling performed during the first trimester (10 to 13 wk) of gestation. In this study, we used an established protocol and isolated placenta-derived mesenchymal stromal cells (PMSCs) from first trimester chorionic villus tissue and transduced them with lentiviral vector encoding the BDD-FVIII gene. We show that gene-modified PMSCs maintain their immunophenotype and multipotency, express, and secrete high levels of active FVIII. PMSCs were then transplanted at embryonic day 14.5 (E14.5) into wild-type fetuses from time-mated pregnant mice. Four days after birth, pups were checked for engraftment, and varying levels of expression of human green fluorescent protein were found in the organs tested. This study shows feasibility of the approach to obtain PMSCs from first trimester chorionic villus tissue, genetically modify them with the FVIII gene, and transplant them in utero for cell-mediated gene therapy of HA. Future studies will involve evaluation of long-term engraftment, phenotypic correction in HA mice, and prevention of FVIII inhibitor development by this approach.

Original languageEnglish (US)
Pages (from-to)130-139
Number of pages10
JournalCell Transplantation
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Factor VIII
Hemophilia A
Mesenchymal Stromal Cells
Placenta
Genes
Transplantation
Transplants
Stem cells
First Pregnancy Trimester
Chorionic Villi
Tissue
Therapeutics
Cell- and Tissue-Based Therapy
Gene therapy
Coagulation
Mesenchymal Stem Cell Transplantation
Chorionic Villi Sampling
Blood
Sampling
Graft Rejection

Keywords

  • chorionic villus sampling
  • factor VIII
  • hemophilia A
  • in utero transplantation (IUT)
  • placenta-derived mesenchymal stromal cells (PMSCs)

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

Cite this

In Utero Transplantation of Placenta-Derived Mesenchymal Stromal Cells for Potential Fetal Treatment of Hemophilia A. / Kumar, Priyadarsini; Gao, Kewa; Wang, Chuwang; Pivetti, Christopher; Lankford, Lee; Farmer, Diana L; Wang, Aijun.

In: Cell Transplantation, Vol. 27, No. 1, 01.01.2018, p. 130-139.

Research output: Contribution to journalArticle

Kumar, Priyadarsini ; Gao, Kewa ; Wang, Chuwang ; Pivetti, Christopher ; Lankford, Lee ; Farmer, Diana L ; Wang, Aijun. / In Utero Transplantation of Placenta-Derived Mesenchymal Stromal Cells for Potential Fetal Treatment of Hemophilia A. In: Cell Transplantation. 2018 ; Vol. 27, No. 1. pp. 130-139.
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abstract = "Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the factor VIII (FVIII) gene leading to deficient blood coagulation. The current standard of care is frequent infusions of plasma-derived FVIII or recombinant B-domain-deleted FVIII (BDD-FVIII). While this treatment is effective, many patients eventually develop FVIII inhibitors that limit the effectiveness of the infused FVIII. As a monogenic disorder, HA is an ideal target for gene or cell-based therapy. Several studies have investigated allogeneic stem cell therapy targeting in utero or postnatal treatment of HA but have not been successful in completely correcting HA. Autologous in utero transplantation of mesenchymal stem cells is promising for treatment of HA due to the naive immune status of the fetal environment as well as its potential to prevent transplant rejection and long-term FVIII inhibitor formation. HA can be diagnosed by chorionic villus sampling performed during the first trimester (10 to 13 wk) of gestation. In this study, we used an established protocol and isolated placenta-derived mesenchymal stromal cells (PMSCs) from first trimester chorionic villus tissue and transduced them with lentiviral vector encoding the BDD-FVIII gene. We show that gene-modified PMSCs maintain their immunophenotype and multipotency, express, and secrete high levels of active FVIII. PMSCs were then transplanted at embryonic day 14.5 (E14.5) into wild-type fetuses from time-mated pregnant mice. Four days after birth, pups were checked for engraftment, and varying levels of expression of human green fluorescent protein were found in the organs tested. This study shows feasibility of the approach to obtain PMSCs from first trimester chorionic villus tissue, genetically modify them with the FVIII gene, and transplant them in utero for cell-mediated gene therapy of HA. Future studies will involve evaluation of long-term engraftment, phenotypic correction in HA mice, and prevention of FVIII inhibitor development by this approach.",
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