Stem Cell Reports. 2018 Nov 3. pii: S2213-6711(18)30435-1. doi: 10.1016/j.stemcr.2018.10.012. [Epub ahead of print]

Patient-Specific iPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A.

Olgasi C¹, Talmon M¹, Merlin S¹, Cucci A¹, Richaud-Patin Y², Ranaldo G¹, Colangelo D¹, Di Scipio F³, Berta GN³, Borsotti C¹, Valeri F⁴, Faraldi F⁵, Prat M¹, Messina M⁴, Schinco P⁴, Lombardo A⁶, Raya A⁷, Follenzi A⁸.

Abstract

We generated patient-specific disease-free induced pluripotent stem cells (iPSCs) from peripheral blood CD34+ cells and differentiated them into functional endothelial cells (ECs) secreting factor VIII (FVIII) for gene and cell therapy approaches to cure hemophilia A (HA), an X-linked bleeding disorder caused by F8 mutations. iPSCs were transduced with a lentiviral vector carrying FVIII transgene driven by an endothelial-specific promoter (VEC) and differentiated into bona fide ECs using an optimized protocol. FVIII-expressing ECs were intraportally transplanted in monocrotaline-conditioned non-obese diabetic (NOD) severe combined immune-deficient (scid)-IL2rγ null HA mice generating a chimeric liver with functional human ECs. Transplanted cells engrafted and proliferated in the liver along sinusoids, in the long term showed stable therapeutic FVIII activity (6%). These results demonstrate that the hemophilic phenotype can be rescued by transplantation of ECs derived from HA FVIII-corrected iPSCs, confirming the feasibility of cell-reprogramming strategy in patient-derived cells as an approach for HA gene and cell therapy.