HONG KONG — A new peptide-based drug delivery system has been shown for the first time to enable therapeutic proteins and possibly other drugs to cross the blood-brain barrier (BBB), which may help in treating multiple sclerosis (MS) and other central nervous system (CNS) disorders such as Alzheimer’s disease and Parkinson’s disease, Korean researchers reported.

A progressive immune-mediated demyelinating disease of uncertain etiology, MS is thought to affect more than 2.3 million people worldwide, according to the U.S. National Multiple Sclerosis Society. While the incidence of MS appears to have increased in recent years, that may be due to greater disease awareness and improved diagnostic capabilities.

Although it is currently incurable, medications are used to modify the course of MS, treat relapses or exacerbations, and manage symptoms. When used in combination with a comprehensive MS management program, such treatments can improve the quality of life for patients.

The FDA has approved a number of different disease-modifying treatments to reduce disease activity and progression in patients with relapsing forms of MS, including relapsing-remitting MS, as well as secondary-progressive and progressive-relapsing MS. Those agents include injectables such as Avonex (interferon beta-1a, Biogen Inc.) and Betaseron (interferon beta-1b, Bayer AG), and oral agents including Gilenya (fingolimod, Novartis AG) and Tecfidera (dimethyl fumarate [DMF], Biogen Inc.).

“Currently used drugs, including the beta-interferons, fingolimod and DMF, are used to suppress lymphocyte activation and migration and to reduce neuronal cell death,” study corresponding author Je-Min Choi, an associate professor of immunology in the Department of Life Science at Hangyang University in Seoul, told BioWorld Asia.

“Other agents, such as Tysabri and Lemtrada [alemtuzumab, Genzyme Corp.], are biological antibodies that respectively target vascular cell adhesion molecule 1 (alpha-4 integrin) and protein CD52 on the lymphocyte surface, thereby preventing lymphocyte migration into the CNS,” added Choi.

In addition to preventing toxic, infectious and other potentially harmful substances from entering the brain, the BBB also blocks the entry of therapeutic agents, particularly large molecules such as proteins and hence many therapeutics that might otherwise be used to treat CNS disorders.

“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,” said Choi. ”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.”

Choi and his Hangyang University research team reported in the Sept. 16, 2015, issue of Nature Communications having used a novel peptide called dNP2 that can enter cells using endocytosis, penetrating the cell membrane and transporting proteins or other drugs into the interior of the cell.

No such peptide delivery system had so far been shown capable of successfully transporting another agent across the BBB. Now, the Korean researchers have shown for the first time that their newly designed dNP2 peptide could do so, by injecting mouse brains with dNP2 attached to a fluorescent marker protein, which could then be seen inside the brain.

“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.”

The researchers therefore attached dNP2 to a fragment of cytotoxic T lymphocyte-associated protein 4 (CTLA4), which inhibits lymphocyte activation, since excessive lymphocyte activation has been shown to be associated with the damage to the brain and spinal cord seen in patients with MS.

“CTLA4 polymorphisms or mutations are associated with MS and in our study we used the cytoplasmic domain of CTLA4 [ctCTLA4] 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 ctCTLA4 protein as a therapeutic drug for autoimmune diseases” such as MS.

The Hangyang University research team then demonstrated that treatment with the dNP2-ctCTLA4 complex was effective in improving health outcomes in mouse models of MS.

“We used an experimental autoimmune encephalomyelitis mouse model, which is a common animal model widely used to represent MS,” said Choi. “Treatment with the dNP2-ctCTLA4 complex was shown to ameliorate pathologic symptoms in these mouse models and to inhibit infiltration of their brains by T helper cells such as Th1 and Th17, which play a major role in the pathology of MS.”

Choi said his group’s in vivo findings suggest that dNP2 may prove to be useful in the treatment of MS and possibly other neurological disorders using protein-based therapeutic agents.

“Many other human brain diseases face the same hurdle of decreased efficiency of potential therapeutics due to the BBB,” he said. In addition to MS, “Alzheimer’s disease, parkinsonism and gliobastomas should be the best diseases to target with the BBB-permeable peptide.”

Given that exciting prospect, Choi said, “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.”

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