The long-term goal of our research program is to develop safe and effective therapies for traumatic brain injury (TBI), which is a major health issue with our military personnel in combat, with estimates of 150,000-300,000 military personnel from Operation Iraqi Freedom and Operation Enduring Freedom suffering some level of TBI. The prevalence of TBI from all causes has been estimated to be 2.5 to 3.7 millions in the USA alone. Currently, there are no drugs available to treat TBI. While TBI illness ranges from mild to severe, moderate TBI is clinically most relevant, and if left untreated it often progresses to severe TBI, which is difficult to treat Hence, there is a genuine need to discover new therapeutic agents for moderate TBI. Adult stem cell therapy including mesenchymal stem cells (MSCs), is under investigation, however, there remains a lack of consensus about the viability of this MSC therapy due to use of different models and techniques, uncertainty about routes of delivery, variable engraftment and the potential for adverse events. Thus, discovering and developing new therapeutic targets remains a major unmet need. We made the striking discovery that expression of chemokine (C-C motif) ligand 20 (CCL20) (MIP3?) is pivotal to inflammation following LFP-TBI (a lateral fluid percussion (LFP) injury model) in rodents, implicating CCL20 as a potential TBI drug target. Our data demonstrates that the acute phase of TBI involves an influx of CCL20-driven inflammatory cells from the periphery that appear to play a role in subsequent neuroinflammation and neurodegeneration. Toward developing a CCL20-based nanogene drug for TBI, we have synthesized multifunctional chitosan- polyethyleneimine (PEI) magnetic micelles (CPMMs) to deliver drugs and genes to the injured brain. In addition, we have found that intranasally delivered MSCs readily migrate to brain and spleen post TBI and reduce reactive astrogliosis in the injured brain. These results have led us to hypothesize that a combinatorial nano-cell therapy comprising intranasal/intravenous administration of CPMMs 1-2 days after TBI to deliver small interfering RNAs (siRNAs) against CCL20 followed by MSC therapy 3-10 days after TBI would respectively, ameliorate acute inflammation and secondary neuronal injury thus providing an effective treatment for moderate TBI.
Three specific aims are proposed to test this hypothesis.
In Aim #1, we will synthesize and characterize TRIC (targeted, reactive oxygen species-inducible CPMM) nanoparticles targeting CCL20 signaling and examine the effects of CCL20 inhibition on LFP-induced TBI pathology.
In Aim #2, we will evaluate the route of delivery that provides a better therapeutic window for MSC delivery and the efficacy of MSC delivery in repairing neurological function deficits in the rat brain after LFP-induced moderate TBI.
In Aim #3, we plan to evaluate therapeutic efficacy of a two-step nano-cell treatment approach for moderate TBI. We will compare the efficacy of TRIC NPs targeting CCL20/CCR6 followed by MSC therapy in ameliorating deficits following moderate TBI and determine mechanisms of action. This highly interdisciplinary and innovative approach of a two-step therapy involving NPs carrying the inhibitor(s) of CCL20 signaling and hMSC therapy for treatment of LFP-induced moderate TBI is highly innovative. We predict that the proposed research will increase our understanding of the potential and role of TRIC-siCCL20 for TBI. All the necessary reagents, methods and collaborations are in place and our investigative team is uniquely poised to conduct the proposed studies.
Traumatic brain injury (TBI) is a major health issue for both military and civilian populations. Currently, there are no drugs available to treat TBI. While TBI severity ranges from mild to severe, moderate TBI is clinically most relevant, and if left untreated it often progresses to severe TBI, which is difficult to treat. Hence, there is a genuine need to discover new therapeutic agents for moderate TBI. This proposal is based on the discovery of a novel target of TBI, CCL20, a chemokine protein that plays a critical role in increasing inflammation in acute TBI and memory loss. Our proposed studies focus on development of a novel combinatorial nano- and cell-integrated therapeutic approach for moderate TBI, which involves nanoparticle driven anti-chemokine therapy to reduce acute inflammation followed by stem cell therapy to remodel neurogenesis and angiogenesis of parenchymal cells in the injured brain.
