This proposal responds to the solicitation of SBIR/STTR PHS 2005-2 for """"""""development of therapies to prevent, arrest or reverse autoimmune neurological disorder such as multiple sclerosis"""""""" by NINDS. Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system; CNS) characterized by demyelination in areas of white matter of the brain and spinal cord that affects more than 350,000 people in the United States (US) and 2.5 million worldwide. Currently, there is no cure for MS, and FDA-approved therapies are focused on ameliorating the inflammatory component of the disease, and not Prevention of the irreversible tissue damage that is the hallmark of MS and the cause of chronic disability. Thus, there is an unmet need for a therapy for MS that not only exerts anti-inflammatory effects, but that also prevents/ameliorates the irreversible neurological damage responsible for the lifelong disability faced by the MS patient. We have developed an anti-inflammatory/neuroprotective peptide, COG133 derived from the receptor binding region of apolipoprotein E (apoE), which 1) suppressed microglial activation and secretion of inflammatory mediators (e.g., TNFa, IL-6, nitric oxide); 2) protected primary culture neurons from glutamate excitotoxicity and oxidative stress; 3) initiated a macrophage signaling cascade and suppressed macrophage activation 4) suppressed the release of systemic, as well as CMS inflammatory cytokines elicited following IV administration of LPS in mice; 5) suppressed secretion of TNF-a and IL-6 in whole human blood is activated with LPS; and 6) exhibited neuroprotective activity in a mouse model of closed head injury. These data indicate that COG133 possesses both anti-inflammatory and neuroprotective effects, and as such may represent the new generation MS therapeutic needed to treat both the inflammatory and neurodegenerative aspects of this disease. As a proof of concept, in this phase I proposal, we will use the murine EAE model of human MS to test whether COG133, given after onset of diseases, can (1) ameliorate neurological impairment in MOG-induced EAE in C57BL/6 mice; and (2) reduce the rate of relapses in PLP-elicited relapsing-remitting model of EAE in SJL mice. The influence of COG133 treatment on peripheral leukocytes infiltration into the CNS, which is the critical step for the pathogenesis of EAE and MS, will also be investigated. In summary, our overall goal is to develop a novel therapy for MS. The anti-inflammatory and neuroprotective effects of COG133 may underlie more powerful, dual therapeutic potential for treatment of MS than current monotherapies with simple anti-inflammatory action. ? ? ?
| Li, Feng-Qiao; Fowler, Kenneth A; Neil, Jessica E et al. (2010) An apolipoprotein E-mimetic stimulates axonal regeneration and remyelination after peripheral nerve injury. J Pharmacol Exp Ther 334:106-15 |
