Safety of intra-articular transplantation of lentivirally transduced mesenchymal stromal cells for haemophilic arthropathy in a non-human primate
- 138 Downloads
Joint bleeding and resultant arthropathy are major determinants of quality of life in haemophilia patients. We previously developed a mesenchymal stromal cell (MSC)-based treatment approach for haemophilic arthropathy in a mouse model of haemophilia A. Here, we evaluated the long-term safety of intra-articular injection of lentivirally transduced autologous MSCs in non-human primates. Autologous bone-marrow-derived MSCs transduced with a lentiviral vector expressing coagulation factor VIII (FVIII) were injected into the left knee joint of cynomolgus monkeys. We first conducted codon optimization to increase FVIII production in the cells. Lentiviral transduction of autologous MSCs resulted in a significant increase of FVIII in the culture supernatant before transplantation. We did not find any tumour generation around the knee structure at 11–16 months after injection by magnetic resonance imaging. The proviral sequence of the simian immunodeficiency virus lentiviral vector was not detected in the heart, lungs, spleen, liver, testis, or bone marrow by real-time quantitative PCR. We confirmed the long-term safety of intra-articular injection of transduced MSCs in a non-human primate. The procedure may be an attractive therapeutic approach for joint diseases in haemophilia patients.
KeywordsCell therapy Haemophilia Lentiviral vector Arthropathy Mesenchymal stromal cells
We acknowledge Dr. Hiroaki Shibata (Tsukuba Primate Research Center) for providing the protocol to isolate monkey MSCs.
This study was supported by the Research Program on HIV/AIDS from the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP17fk0410306h0003 and JP18fk0410017h0001.
Conflict of interest
Dr Ohmori received research support from Bayer, Dai-ichi Sankyo, Novo Nordisk, and CSL Behring outside of this study. M.I. and T.T. are employees of ID Pharma Inc. All other authors declare no competing financial interests.
- 1.Young G. New challenges in hemophilia: long-term outcomes and complications. Hematol Am Soc Hematol Educ Program. 2012;2012:362–8.Google Scholar
- 3.Marijke van den Berg H. Preventing bleeds by treatment: new era for haemophilia changing the paradigm. Haemophilia. 2016;22(Suppl 5):9–13.Google Scholar
- 7.Hanley J, McKernan A, Creagh MD, Classey S, McLaughlin P, Goddard N, et al. Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia: a United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) guideline. Haemophilia. 2017;23:511–20.CrossRefPubMedGoogle Scholar
- 13.Mimuro J, Muramatsu S, Hakamada Y, Mori K, Kikuchi J, Urabe M, et al. Recombinant adeno-associated virus vector-transduced vascular endothelial cells express the thrombomodulin transgene under the regulation of enhanced plasminogen activator inhibitor-1 promoter. Gene Ther. 2001;8:1690–7.CrossRefPubMedGoogle Scholar
- 14.Ohmori T, Mimuro J, Takano K, Madoiwa S, Kashiwakura Y, Ishiwata A, et al. Efficient expression of a transgene in platelets using simian immunodeficiency virus-based vector harboring glycoprotein Ibalpha promoter: in vivo model for platelet-targeting gene therapy. FASEB J. 2006;20:1522–4.CrossRefPubMedGoogle Scholar
- 17.Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. 2011;9:CD003429.Google Scholar