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

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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.

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Funding

This work was supported by a research grant from Sanofi-Aventis U.S. to J.M.K. and FJQ, by a grant from King Abdulaziz City for Science and Technology to J.M.K. and FJQ, by National Institutes of Health grants HL095722, and by the Fundação para a Ciência e a Tecnologia through MIT-Portugal-TB/ECE/0013/2013 (to J.M.K.). V.R. received support from an educational grant from Mallinckrodt Pharmaceuticals (A219074) and by a fellowship from the German Research Foundation (DFG RO4866 1/1).

Author information

Author notes

  1. Oren Levy, Veit Rothhammer and Ivan Mascanfroni contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA

    Oren Levy, Zhixiang Tong, Rui Kuai, Michael De Biasio, Helia Safaee, Juliet Musabeyezu, Martina Heinelt, Yuka Milton, Heidi Kuang, Haoyue Lan & Jeffrey M. Karp

  2. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Veit Rothhammer, Ivan Mascanfroni, Ada Yeste, Jessica E. Kenison & Francisco J. Quintana

  3. Centre of Excellence for Biomedicine, Brigham and Women’s Hospital, Boston, MA, USA

    Rui Kuai, Francisco J. Quintana & Jeffrey M. Karp

  4. Department of Drug Metabolism and Pharmacokinetics, Sanofi R&D, Waltham, MA, USA

    Qingping Wang

  5. Global Research Program and Portfolio Management, Sanofi-Genzyme, Cambridge, MA, USA

    Tahir Majid

  6. Sanofi R&D, In Vitro Pharmacology, Integrated Drug Discovery, Centre de Recherche Vitry-Alfortville, Vitry-Sur-Seine, France

    Christelle Perrault

  7. Genzyme R&D, Neuroimmunology Research, Framingham, MA, USA

    William Siders

  8. Sanofi R&D, Translational Sciences, Centre de Recherche Vitry-Alfortville, Vitry-Sur-Seine, France

    Marie-Christine Multon

  9. Sanofi R&D, Biologics Research, Cambridge, MA, 02139, USA

    Jonathan Rothblatt

  10. Developmental Medicine Department, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia

    Salam Massadeh & Manal Alaamery

  11. Centre of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia

    Salam Massadeh, Manal Alaamery & Ali H. Alhasan

  12. National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia

    Ali H. Alhasan

  13. The Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Francisco J. Quintana & Jeffrey M. Karp

Authors
  1. Oren Levy
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  2. Veit Rothhammer
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Contributions

O.L., V.R., and I.M. co-wrote the paper, designed experiments, performed experiments, and analyzed and interpreted data. Z.T., R.K., M.B., Q.W., T.M., and C.P. designed experiments, performed experiments, and analyzed and interpreted data. A.Y., J.K., H.S., J.M., M.H., Y.M., H.K., and H.L. performed experiments and analyzed data. W.S., M.M., J.R., M.A., S.M., and A.A. designed experiments and interpreted data. F.J.Q. and J.M.K. co-wrote the paper, designed experiments, and interpreted data.

Corresponding authors

Correspondence to Francisco J. Quintana or Jeffrey M. Karp.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted and ethical approval was obtained from the Institutional Animal Care and Use Committee at Harvard Medical School.

Conflict of interest

Q. W., T. M., C.P., W. S., M.-C. M., and J.R. are employed by Sanofi. JMK has been a paid consultant and or equity holder for companies including Stempeutics, Sanofi, Celltex, LifeVaultBio, Tissium, Takeda, Skintifique, Alivio Therapeutics, Altrix Bio, Ligandal, Vyome, Camden Partners, Stemgent, Gyro Gear, Mirakel, Landsdowne Labs, Biogen, Pancryos, Element Biosciences, Frequency Therapeutics, Molecular Infusions, Quthero, and Mesoblast. JMK is also an inventor on a patent that was licensed to Mesoblast. JMK holds equity in Frequency Therapeutics, a company that has licensed IP generated by JMK that may benefit financially if the IP is further validated. The interests of JMK were reviewed and are subject to a management plan overseen by his institutions in accordance with its conflict of interest policies.

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Levy, O., Rothhammer, V., Mascanfroni, I. et al. A cell-based drug delivery platform for treating central nervous system inflammation. J Mol Med 99, 663–671 (2021). https://doi.org/10.1007/s00109-020-02003-9

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