EAGER: Unraveling the mechanism and the role of anti- inflammatory nanoparticles in multiple sclerosis model

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PI: Seal, SudiptaProposal Number: 1261956Multiple Sclerosis (MS) is a disabling neurological disorder affecting 2.5 million patients worldwide including 400,000 Americans. MS often results in severe disability including the inability to walk, impaired vision or in some cases blindness and cognitive dysfunction. Although immunomodulatory therapies became available but are partially effective, therefore, there is a continuing need to develop more effective treatment strategies to combat this disabling disease. Experimental autoimmune encephalitis (EAE) is a well accepted an animal model for MS which can be induced in mice using myelin protein like MOG (Myelin Oligodendrocyte Glycoprotein) or PLP (proteolipid protein). Recently nanotechnology based apporacheshave shown a lot of promise in various therapies. Among various nanoparticles, cerium oxide nanoparticles (nanoceria; NCe) are very unique, possess excellent antioxidant properties and act as potent, regenerative free radical scavengers. Since inflammation play key role in axonal loss and demyelinating events underlying MS pathology and contribute to disability in MS patients, we examined the effect of NCe on ROS and inflammation in macrophage and T cells and found that NCe treatment quenches ROS generation, inhibits iNOS and COX2 (inflammatory mediators) This study will be first study to show the therapeutic potential of nanoparticles to revert the disability in EAE, a model of MS. Hypothesis/Objectives: Engineered mixed valence cerium oxide nanoparticles with antioxidant and anti-inflammatory properties will suppress disease in animal models of MS by modulating adaptive immune responses and may provide neuroprotection (inhibiting axonal loss and demyelination) in the CNS, thereby reverting disability/paralysis. We propose the following aims: 1) Engineering of NCe and its full scale characterization for biocompatibility, 2) Examine the potential of NCe on adaptive immune response and reverting disability in mouse models mimicking chronic and relapsing remitting form of MS. Intellectual Merit: This study, if successful, would provide the groundwork and rationale for introducing this therapy to the MS clinical arena. The main advantages of using this nanotechnology based therapy are: 1): NCe exhibits regenerative free radical scavenging and excellent antioxidant properties. 2): NCe acts as anti-inflammatory molecule in in-vitro as well as in-vivo mice model. 3): NCe treatment protects neurons against oxidative stress and prolongs their life span in culture. 4): Administration of NCe in mouse model is safe and shows no toxicity even with significantly higher doses. 5): More importantly, due to the regenerative property of NCe, it will limit the repeated doses during therapeutic studies in vivo. Significance/Transformative Concept This EAGER proposal focuses on the science behind developing nano rare earth particles and its mechanism in reverting disability in animal models of MS by neutralizing oxidative stress induced generated by inflammation in CNS. Broader Impact: The proposed study has potential to take nanotechnology mediated pharmacological treatment to a new level, if successful; it can provide effective therapies for MS. The finding will not be just confined to these diseases but has broad implications to other neurodegenerative diseases, which involve oxidative stress and inflammation. In this concept project we proposed to explore possible protection of NCe in reverting paralysis in animal models of MS which can have a big societal impact on the millions of people worldwide on MS treatment.