A cell-based drug delivery platform for treating central nervous system inflammation PMID: 33398468

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
14. Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
15. The Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
16. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA. [email protected].
17. Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
18. The Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
# Contributed equally.

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.