2. Academic Validation
  3. A cell-based drug delivery platform for treating central nervous system inflammation

A cell-based drug delivery platform for treating central nervous system inflammation

  • J Mol Med (Berl). 2021 May;99(5):663-671. doi: 10.1007/s00109-020-02003-9.
Oren Levy # 1,  Veit Rothhammer # 2,  Ivan Mascanfroni # 2,  Zhixiang Tong 1,  Rui Kuai 1 3,  Michael De Biasio 1,  Qingping Wang 4,  Tahir Majid 5,  Christelle Perrault 6,  Ada Yeste 2,  Jessica E Kenison 2,  Helia Safaee 1,  Juliet Musabeyezu 1,  Martina Heinelt 1,  Yuka Milton 1,  Heidi Kuang 1,  Haoyue Lan 1,  William Siders 7,  Marie-Christine Multon 8,  Jonathan Rothblatt 9,  Salam Massadeh 10 11,  Manal Alaamery 10 11,  Ali H Alhasan 11 12,  Francisco J Quintana 13 14 15,  Jeffrey M Karp 16 17 18
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA.
  • 2 Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 3 Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA.
  • 4 Department of Drug Metabolism and Pharmacokinetics, Sanofi R&D, Waltham, MA, USA.
  • 5 Global Research Program and Portfolio Management, Sanofi-Genzyme, Cambridge, MA, USA.
  • 6 Sanofi R&D, In Vitro Pharmacology, Integrated Drug Discovery, Centre de Recherche Vitry-Alfortville, Vitry-Sur-Seine, France.
  • 7 Genzyme R&D, Neuroimmunology Research, Framingham, MA, USA.
  • 8 Sanofi R&D, Translational Sciences, Centre de Recherche Vitry-Alfortville, Vitry-Sur-Seine, France.
  • 9 Sanofi R&D, Biologics Research, Cambridge, MA, 02139, USA.
  • 10 Developmental Medicine Department, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
  • 11 Centre of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
  • 12 National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
  • 13 Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@bwh.harvard.edu.
  • 14 Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA. fquintana@bwh.harvard.edu.
  • 15 The Broad Institute of Harvard and MIT, Cambridge, MA, USA. fquintana@bwh.harvard.edu.
  • 16 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA. jeffkarp@mit.edu.
  • 17 Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA. jeffkarp@mit.edu.
  • 18 The Broad Institute of Harvard and MIT, Cambridge, MA, USA. jeffkarp@mit.edu.
  • # Contributed equally.
PMID: 33398468 DOI: 10.1007/s00109-020-02003-9
Abstract

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.

Keywords

Drug delivery; Mesenchymal stem cells; Multiple sclerosis; Ro-31-8425.

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