Serpin Modulation of Inflammatory Vasculitis;Potential for Immunomodulatory Therapy The broad challenge areas applicable for this research proposal are 1) 15-OD(ORDR)-101* Pilot projects for prevention, early detection and treatment of rare diseases, 2) 15-NS-104 Early-stage therapy development, or 3) NSP - 15-NS-103 Demonstration of """"""""proof-of-concept"""""""" for a new therapeutic approach in a neurological disease. In broad strokes, the proposal presented here is a translational research study that addresses the more rare inflammatory vasculitic syndromes, Takayasu's disease (TKD) and Giant Cell Temporal Arteritis (GCTA). This work is designed to identify new molecular targets, to examine the feasibility of a new approach to treatment of inflammatory vasculitis, and to provide 'proof of principal'for therapeutic intervention with a new class of anti-inflammatory serine protease inhibitor (serpin) therapeutics. Takayasu's Disease (TKD) and Giant Cell Temporal Arteritis (GCTA) are pan-vasculitic syndromes, causing devastating disease with inflammatory cell mediated damage to all tissue layers of medium and large vessel arteries. Inflammatory vasculitis (IVS) ranges from rarer disorders such as TKD (2.6/million) and GCTA (20-200/100,000) to the arterial inflammation associated with atherosclerosis and aneurysm formation. Inflammatory cell invasion is characterized by invading adventitial and medial dendritic cells, macrophage, T lymphocytes, specifically T helper 1 (TH1) subpopulations, and giant cells, with attendant elastic layer degradation. This inflammation accelerates plaque formation and arterial occlusion or conversely arterial aneurysm formation, manifesting as sudden loss of vision, stroke, myocardial ischemia, aortic arch syndrome, and aneurysm rupture. Once diagnosed, the IVS are considered medical emergencies. Current treatment is limited to ASA and prednisone and long-term steroid treatment is associated with significant adverse events in up to 60% of patients. Other newer medical treatments such as TNF inhibitors and methotrexate have had only partial success in limited subsets of patients. Surgical interventions for occlusive or aneurysmal vascular changes is based upon watchful surveillance with potential high associated morbidity and mortality. Even with treatment, disease can progress and recur with cessation of treatment. New therapeutic approaches are thus needed and treatments targeting inflammatory cell activation and invasion have potential to prevent progression or to stabilize vascular areas at risk. Serine proteases in the thrombolytic cascade have been identified as activators of inflammatory cell responses in atherosclerosis and aneurysm models. Two innovative therapeutic approaches, based upon the infusion of serpins, one derived from a myxoma virus, Serp-1, and one mammalian serpin, neuroserpin (NSP), have been investigated in our research laboratory with proven anti-inflammatory actions in atherosclerosis (Fig/s 2 &3), transplant vasculopathy, and collagen-induced arthritis in animal models. NSP is expressed by neurons, monocytes, and multiple organs, and is reported to reduce stroke volume in rodent models and in recent work from our lab, reduced transplant vasculopathy (Fig 1, Research Proposal). These serpins target protease cascades in the clot dissolving thrombolytic (uPA, tPA for Serp-1 and NSP;plasmin for Serp-1 ) and clot forming thrombotic pathways (fXa for Serp-1). These proteases have been associated with increased inflammatory cell invasion and matrix degradation both by our group and also other investigators. Treatment with either Serp-1 or NSP alters the balance of TH1 and TH2 activation with reduced TH1. Serp-1 represents a new class of virus-derived anti-inflammatory immunomodulatory therapeutic agents and we have recently successfully tested Serp-1 in a phase 2A clinical trial in acute coronary syndrome patients with a significant reduction in circulating markers for inflammation. No significant adverse events were detected (proprietary information, Viron Therapeutics, Inc. London, Canada). In summary, these studies are designed to assess the potential role of thrombolytic proteases, receptors, and regulatory serpins, specifically uPA, uPAR, and PAI-1, as molecular targets in Inflammatory Vasculitic (TKD and GCTA) disease and to assess the potential for serpin-derived therapies. This work will have potential for broad application to other forms of inflammatory vasculitis such as more common atherosclerotic plaque and aneurysm formation. With these studies we will conduct an intensive analysis into the role of thrombolytic serine proteases, serpins and receptors in mouse models of aggressive vasculitic disorders, specifically Giant Cell Temporal Arteritis (GCTA) and Takayasu's Disease (TKD), that cause sudden blindness, pulseless vessel occlusions, strokes, heart attacks, and aneurysms. The thrombolytic serine protease enzymes in the clot lysis pathway initiate collagen breakdown and aneurysm formation and serine proteinase inhibitors (serpins) protect against protease activation. We will test the therapeutic potential of two anti-inflammatory serpins for treatment of GCTA and TKD, and their capacity to actively modify T Helper (TH) cell responses. We have successfully tested one of these serpins, Serp-1, in a small phase 2A clinical trial for anti-inflammatory activity in unstable coronary syndromes (Viron Therapeutics, Inc;proprietary information).
With these studies we will conduct an intensive analysis into the role of thrombolytic serine proteases, serpins and receptors in mouse models of aggressive vasculitic disorders, specifically Giant Cell Temporal Arteritis (GCTA) and Takayasu's Disease (TKD), that cause sudden blindness, pulseless vessel occlusions, strokes, heart attacks, and aneurysms. The thrombolytic serine protease enzymes in the clot lysis pathway initiate collagen breakdown and aneurysm formation and serine proteinase inhibitors (serpins) protect against protease activation. We will test the therapeutic potential of two anti-inflammatory serpins for treatment of GCTA and TKD, and their capacity to actively modify T Helper (TH) cell responses. We have successfully tested one of these serpins, Serp-1, in a small phase 2A clinical trial for anti-inflammatory activity in unstable coronary syndromes (Viron Therapeutics, Inc;proprietary information).
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