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AsianScientist (Sep. 22, 2015) – Researchers have discovered a cell permeable peptide that can efficiently deliver a conjugated protein through the tightly organized blood brain barrier (BBB). Publishing their findings in Nature Communications, the researchers also showed that the peptide was effective in treating experimental mouse models for central nervous system (CNS) inflammatory disease.
Multiple sclerosis (MS) is a demyelinating disease which affects the brain and spinal cord of the CNS. The causes of MS are currently being teased apart, and though no cure currently exists on the market, there are many drugs available to improve the quality of life of patients.
“Drugs on the market such as beta-interferons and dimethyl fumarate (DMF), are used to suppress lymphocyte activation, migration and reduction of neuronal cell death,” said Associate Professor Choi Je-Min, a corresponding author of the study from the Hanyang University Department of Life Science.
However, a major barrier that prevents effective treatment of such diseases is the efficiency of drug delivery across the BBB.
“The BBB is a barrier system that selectively allows the passage of water, some gases and the transport of glucose and amino acids. As such, the BBB represents a huge hurdle to drug delivery into the brain for the treatment of CNS diseases,” Choi told Asian Scientist Magazine.
“Therefore, immune modulatory therapeutic proteins or small molecules that might otherwise be suitable for treating MS are limited by their inability to cross the BBB.”
In the present study, Choi and his colleagues identified a peptide that would be able to conjugate, penetrate and deliver proteins efficiently into cells. Called dNP2, the peptide was more efficient than other proteins tested at delivering its cargo into primary cells in vitro, a step that normally limits the clinical application of such delivery peptides.
The researchers also conjugated dNP2 to fluorescent proteins to allow for peptide tracing after intravenous injections into mice. They observed that dNP2 was efficiently delivered intracellularly to both brain and spinal cord tissue.
“This showed that the dNP2-protein complex had successfully crossed the BBB,” said Choi. “If the carrier peptide and the cargo protein complex could be successfully delivered into the brain, we could deliver therapeutic cargo molecules into the brain, which would have huge potential for therapeutic use in human CNS diseases.”
Following the identification of a delivery peptide, Choi suggested the conjugation of dNP2 to the CTLA-4 protein, which has been shown to negatively regulate T cell activation, as a novel therapeutic treatment model.
“CTLA-4 polymorphisms or mutations are associated with MS and in our study we used the cytoplasmic domain of CTLA-4 (ctCTLA-4) as a therapeutic protein, which has never previously been used for treating MS,” Choi said, adding, “We are the only team to have developed the ctCTLA-4 protein as a therapeutic drug for autoimmune diseases such as MS.”
Using this dNP2-ctCTLA-4 conjugate on an experimental autoimmune encephalomyelitis mouse model, a common animal model widely used to represent MS, pathological symptoms such as the infiltration of activated T cells and demyelination were reduced.
Considering other CNS diseases that encounters the same BBB hurdle such as Alzheimer’s and Parkinson’s disease, the use of dNP2 as a potential therapeutic agent may be highly effective.
“We are currently performing preclinical testing of the dNP2-ctCTLA4 complex in MS in the hope of developing it as a successful therapeutic agent in human neurodegenerative disease.” Choi remarked.
The article can be found at: Lim et al. (2015) dNP2 is a Blood–Brain Barrier-Permeable Peptide Enabling ctCTLA-4 Protein Delivery to Ameliorate Experimental Autoimmune Encephalomyelitis.
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Source: Asian Scientist Magazine.
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