IQuity Labs, Inc. — Department of Health and Human Services SBIR Phase I: NIAID

Description

No other group of diseases encompasses a greater pathophysiology than do the rheumatic diseases Spanning multiple organ systems clinical decisions often rely on coordinated efforts from primary care providers and rheumatologists to rule in or rule out differential diagnoses when treating inflammatory conditions such as rheumatoid arthritis RA and systemic lupus erythematosus SLE RA is a symmetric inflammatory peripheral polyarthritis leading to deformity of joints via erosion of bone and surrounding cartilage SLE can affect virtually any organ leading to fatigue fever myalgia weight change and complications associated with renal central nervous system and hematologic systems can be life threatening RA and SLE are diagnosed through clinical judgment after excluding alternative diagnoses In the case of both diseases individual laboratory tests are effective only in a portion of the disease population In RA testing for rheumatoid factor and anti CCP antibodies provide very important information when positive However these two analytes remain negative in of patients and continue to be negative throughout diagnostic follow up in of patients with RA Further erythrocyte sedimentation rates ESR and c reactive protein CRP levels are generally strongly correlated with radiographic findings of joint damage These measurements however can be elevated by other infectious and inflammatory processes that are not specific for RA or can be altered in the case of ESR by acute phase reactants from malignancy tissue injury or trauma In SLE exclusion of markers diagnostic for RA coupled with presence of markers measuring antinuclear antibodies ANA and followed by assays measuring double stranded DNA dsDNA anti Sm anti Ro SSA anti La SSB anti U RNP or antiribosomal P are frequently used Across these analyses the sensitivity and specificity for these laboratory measurements vary greatly and many have high specificity to rule in SLE but lack sensitivity as these diagnostic markers can be found in other disorders For instance anti Ro anti La are found in Sjogrenandapos s syndrome and anti U RNP is frequently associated with mixed connective tissue disease As a physician colleague pointed out it is difficult to diagnose a negative Thus diagnostic approaches for both RA and SLE often rely on multiple independent laboratory tests combined with clinical observation Distinguishing between these diseases is important as the treatment procedures for these diseases are different Time is a frequent factor in the diagnosis of these diseases and tools are needed to facilitate earlier diagnosis as treatment for autoimmune diseases are highly effective and early initiation of therapy leads to the best outcomes Misdiagnosis of these conditions is also not uncommon Another common disease seen by rheumatologists is fibromyalgia syndrome FMS FMS is a common cause of widespread musculoskeletal pain that affects tendons ligaments and muscle FMS is difficult to diagnose and treat and a critical clinical point is that FMS is not explained by another rheumatic or systemic disorder Thus FMS is a diagnosis of exclusion once other etiologies have been considered and excluded RA and SLE are two diseases that must be eliminated from the differential diagnosis Given the complicated diagnostic process these patients are often forced to endure recent studies have also suggested that healthcare dollars are saved post diagnosis and patient outcomes improve To date there is no laboratory test that can determine presence or absence of these three conditions from a single blood sample The question of whether or not disease classifiers capable of providing clinically useful information could be built based upon disease specific expression levels of mRNAs in whole blood has been a subject of research for greater than ten years Many disease specific gene expression signatures have been identified in the research lab A few of these have even progressed into commercially viable diagnostic tests notably for systemic sclerosis Long non coding RNAs lncRNA are recently discovered regulatory RNA molecules that do not code for proteins but influence a vast array of biological processes In vertebrates the number of lncRNA genes greatly exceeds the number of protein coding genes It is also thought that lncRNAs drive greater biologic complexity between vertebrates and invertebrates These lncRNAs also show much greater cell type specific expression patterns than mRNAs Humans also develop many more complex diseases than other organisms As such our data presented in preliminary studies support the notion that disease associated lncRNAs exhibit far greater differences in expression than disease associated mRNAs In this application we propose to explore the hypothesis that lncRNAs are better biomarkers of human disease than mRNAs Here we will focus on FMS and rheumatic diseases as disease categories and have identified FMS and rheumatic disease associated differentially expressed lncRNAs Study of lncRNAs in human autoimmune disease is in its infancy and exploration of lncRNAs as biomarkers of autoimmune disease has not been previously addressed We propose the following specific aim To identify annotated and novel lncRNAs differentially expressed among CTRL FMS RA and SLE and assess their function as biomarkers to distinguish FMS RA and SLE subjects from healthy subjects and subjects with other rheumatic diseases Diagnosis of fibromyalgia syndrome and other rheumatic diseases can be a difficult long and costly process and misdiagnosis of these diseases is not uncommon Long non coding RNAs lncRNA are a new class of regulatory RNA molecules that exhibit high degrees of cell type specific expression The hypothesis we will test in this application is that measurement of expression of disease specific lncRNAs in rheumatic diseases and fibromyalgia syndrome will have greater utility to provide meaningful clinical information to health care providers faced with these diagnostic dilemmas than measurement of disease specific mRNAs