dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis

• Published in: Nature communications Vol. 6; no. 1; p. 8244
• Main Authors: Lim, Sangho, Kim, Won-Ju, Kim, Yeon-Ho, Lee, Sohee, Koo, Ja-Hyun, Lee, Jung-Ah, Yoon, Heeseok, Kim, Do-Hyun, Park, Hong-Jai, Kim, Hye-Mi, Lee, Hong-Gyun, Yun Kim, Ji, Lee, Jae-Ung, Hun Shin, Jae, Kyun Kim, Lark, Doh, Junsang, Kim, Hongtae, Lee, Sang-Kyou, Bothwell, Alfred L M, Suh, Minah, Choi, Je-Min
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15.09.2015; Nature Pub. Group
• Subjects: Animals; Antigens; Blood vessels; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain research; Carrier Proteins - metabolism; Cell-Penetrating Peptides - metabolism; Central nervous system; CTLA-4 Antigen - immunology; Cytotoxicity; Disease Models, Animal; Drug delivery systems; Drugs; Efficiency; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - immunology; HeLa Cells; Humans; In Vitro Techniques; Inflammation; Jurkat Cells; Kinases; Ligands; Localization; Lymphocytes; Mice; Mice, Inbred C57BL; Multiple sclerosis; Nervous system; Peptide Fragments - metabolism; Peptides; Permeability; Proteins; Science; Spinal cord; T-Lymphocytes - immunology; Th17 Cells - immunology; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9244

Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood-brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood-brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.