R01AR078340

Influence of NT5C1A Antibodies on Disease Progression, Clinical Phenotype, and Blood and Muscle Biomarkers in Sporadic Inclusion Body Myositis - A Prospective Evaluation - Project Summary

Sporadic Inclusion Body Myositis (SIBM) is a rare disorder of aging Americans, causing asymmetric muscle weakness and severe disability and morbidity. It is currently untreatable and poorly understood. The prevalence of SIBM is likely to increase as the proportion of the United States population above the age of 65 years continues to grow.

A major barrier to clinical trials in SIBM has been the lack of full understanding of the natural history of the disease. It remains to be determined whether the rates of disease progression are uniform and whether the various biomarkers associated with SIBM (anti-NT5C1A antibodies, variant T-cell populations) influence the natural history and disease behavior. Given the slow rate of disease progression, such observations cannot be made in the context of a routine clinical trial, and such studies need to be done as a separate stand-alone observational study.

To address these unmet needs, we propose a prospective study with four specific aims.

Aim 1: To determine for the first time whether C1A antibodies mediate disease progression over a two-year interval in patients with SIBM.

Aim 2: To perform a detailed morphological, histochemical, and immunohistochemical analysis of fresh muscle biopsy specimens obtained from a subset of patients with SIBM.

Aim 3: To characterize the distribution of "immunosenescent" lymphocytes in circulating blood from patients with SIBM.

Aim 4: To quantify the decline in the respiratory function of SIBM patients.

The significance of our proposed study is 1) to allow for a detailed characterization of the disease progression in SIBM over a two-year period and 2) to explore the relationship of a number of biomarkers associated with SIBM and their influence on disease behavior and progression.

Upon completion of these aims, we will 1) understand the disease phenotype, including the pattern of respiratory involvement, and disease progression in SIBM better and understand the influence of serum antibodies to NT5C1A antibodies on the natural history and disease behavior; 2) define differences in serum variant T-cells and cytokine signatures in SIBM patients and their influence on disease progression and behavior; and 3) understand muscle pathology and immune cell distribution in SIBM patients and its relationship to NT5C1A antibodies.

These findings may influence future trial design in SIBM. Finally, we will have created a thirteen-site consortium of myositis treatment centers that will be ready to adopt quickly any future clinical trials aimed at changing the course of SIBM.

Irvine University Of California

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Orange, California 928683217 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 267% from $1,139,940 to $4,186,266.