Patented Biomarkers in Inflammation and Autoimmune Disease

To date, Source MDx has developed Precision Profiles™ for eight types of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, lupus, osteoarthritis, psoriasis, Crohn's disease, transplant rejection and ulcerative colitis. Precision Profiles™ in Autoimmune Disease encompass over 350 technically validated gene assays that have been selected through extensive literature review, in-house pilot studies, grant-funded studies, collaborative studies with pharmaceutical partners as well as a strong corporate background in the general knowledge of inflammation and immunity. An additional set of 250 inflammation and immune response-related target genes, including, cytokines, chemokines, growth factors and cell signaling molecules provides a comprehensive molecular view of immune system function and dysfunction, including over activity and suppression.

Clinical Studies in Inflammation and Autoimmune Disease

Since 2002, Source MDx has conducted over twenty prospective clinical studies in eight types of autoimmune disease including rheumatoid arthritis, multiple sclerosis, lupus, osteoarthritis, psoriasis, Crohn's disease, transplant rejection and ulcerative colitis. Collectively, these studies involved over 1,700 disease patients and healthy normal control subjects. Furthermore, these studies served to characterize subjects in a variety of disease conditions such as those that are not controlled by standard therapeutics, those that are under control by targeted therapeutics, those that are considered in a state of exacerbation or flare, as well as those that have been wash-out of therapy.

These clinical studies have resulted in a portfolio of diagnostic patents in autoimmune disease that claim to:

• Distinguish newly diagnosed patients with autoimmune disease from healthy normal subjects or from subjects with other types of autoimmune disease.
• Characterize response to targeted therapies as well as over suppression of the immune system as a result of targeted therapies.

Active prospective clinical studies in autoimmune disease include a recently announced Source MDx and Brigham and Women’s Hospital partnership in multiple sclerosis (MS). The principal investigators for the study are Phil De Jager, M.D., Ph.D., Associate Professor at the Center for Neurologic Diseases at Brigham and Women’s and Harvard Medical School, and David Hafler, M.D., Professor of Neurology at Harvard Medical School. The goal of this study is to characterize whole blood gene expression associated with MS disease status (relapse versus stable disease) and response/non-response to Avonex and Glatiramer Acetate treatment. This collaborative study is part of ongoing research being conducted by Dr. De Jager and Dr. Hafler along with colleagues at the International Multiple Sclerosis Genetics Consortium. This group has completed the largest replicated whole genome associated study in MS, evaluating more than 1,000 disease subjects. This work has resulted in the identification of two new genetic variations associated with MS (New England Journal of Medicine "Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study," August 30, 2007) and represents seminal work in the MS field. It is anticipated that this partnership will result not only in a better understanding of the unpredictable nature of this complex disease but will also provide physicians with molecular tools to better diagnose patients, select treatment and assess the overall course of the disease.

Link between Inflammation and Autoimmune Disease

Source MDx has always recognized and continues to investigate the central role inflammation plays in the pathogenesis of autoimmune disease. This concept is well supported in the literature as evidenced by basic research in the link between chronic inflammation and autoimmune disease, including global strategies in dampening inflammation for the treatment of such diseases. Some relevant references surrounding this topic are provided below.

• Brentano F et al. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol. 2005 Feb;233(2):90-6.
• Brod SA et al. Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases interleukin-6 production in multiple sclerosis. Neurology. 1996 Jun;46(6):1633-8.
• Carroll MC. A protective role for innate immunity in systemic lupus erythematosus. Nat Rev Immunol. 2004 Oct;4(10):825-31.
• Crane IJ et al. Th1 and Th2 lymphocytes in autoimmune disease. Crit Rev Immunol. 2005;25(2):75-102.
• Crow MK. Interferon pathway activation in systemic lupus erythematosus. Curr Rheumatol Rep. 2005 Dec;7(6):463-8.
• Crow MK. Type I interferon in systemic lupus erythematosus. Curr Top Microbiol Immunol. 2007;316:359-86.
• Deane JA et al. Nucleic acid-sensing TLRs as modifiers of autoimmunity. J Immunol. 2006 Nov 15;177(10):6573-8.
• Fairhurst AM et al. Systemic lupus erythematosus: multiple immunological phenotypes in a complex genetic disease. Adv Immunol. 2006;92:1-69.
• Falgarone G et al. Role for innate immunity in rheumatoid arthritis. Joint Bone Spine. 2005 Jan;72(1):17-25.
• Goronzy JJ et al. Rheumatoid arthritis. Immunol Rev. 2005 Apr;204:55-73.
• Gran B et al. T cells, cytokines, and autoantigens in multiple sclerosis. Curr Neurol Neurosci Rep. 2001 May;1(3):263-70.
• Hendriks JJ et al. Macrophages and neurodegeneration. Brain Res Brain Res Rev. 2005 Apr;48(2):185-95.
• Jara LJ et al. Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases. Autoimmun Rev. 2006 Mar;5(3):195-201. Epub 2005 Jul 26.
• Karni A et al. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J Immunol. 2006 Sep 15;177(6):4196-202.
• Klinman D. Does activation of the innate immune system contribute to the development of rheumatoid arthritis? Arthritis Rheum. 2003 Mar;48(3):590-3.
• Krieg AM et al. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev. 2007 Dec;220:251-69.
• Kyttaris VC et al. Systems biology in systemic lupus erythematosus: integrating genes, biology and immune function. Autoimmunity. 2006 Dec;39(8):705-9.
• Liu H et al. Phagocytes: mechanisms of inflammation and tissue destruction. Rheum Dis Clin North Am. 2004 Feb;30(1):19-39, v.
• Malmstrøm V et al. The additive role of innate and adaptive immunity in the development of arthritis. Am J Med Sci. 2004 Apr;327(4):196-201.
• O'Brien K et al. Role of the innate immune system in autoimmune inflammatory demyelination. Curr Med Chem. 2008;15(11):1105-15.
• Oldstone MB. Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept. Curr Top Microbiol Immunol. 2005;296:1-17.
• Pascual V et al. Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol. 2006 Dec;18(6):676-82. Epub 2006 Oct 2.
• Rifkin IR et al. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev. 2005 Apr;204:27-42.
• Ristori G et al. Global immune disregulation in multiple sclerosis: from the adaptive response to the innate immunity. J Neuroimmunol. 2000 Jul 24;107(2):216-9.
• Rönnblom L et al. The innate immune system in SLE: type I interferons and dendritic cells. Lupus. 2008;17(5):394-9.
• Theofilopoulos AN et al. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307-36.
• Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol. 2008 Mar;255 Suppl 1:3-11.