Compare the genes present in IBM muscle cells to those present in healthy/control muscle cells (2021)

Chiseko Ikenaga MD, PhD
Johns Hopkins University

Chiseko Ikenaga MD, PhD has been granted $100,000 in fellowship support over a two year period at Johns Hopkins University.  Dr. Ikenaga’s project seeks to identify potential novel biomarkers for Inclusion Body Myositis.   This project will compare the genes present in IBM muscle cells to those present in healthy/control muscle cells.  If successful, this research may identify genes that are markers for the disease and that could enable earlier diagnosis and a means to measure disease severity over time.

A randomized, double-blind, controlled Phase III trial of Sirolimus in sporadic IBM (2020) 

Mazen Dimachkie, MD
University of Kansas
Dr. Dimachkie works with international IBM investigators on a randomized, double-blind, controlled Phase III trial of Sirolimus in sporadic IBM. The funding will be used over the course of two years, collaborates with research in France and Australia, and supports U.S. study sites Kansas and Maryland.

A Pilot study of CD8 T-cell imaging with 89Zr-Df-IAB22m2C in IBM (2018)

Steven Greenberg, MD
Brigham and Women’s Hospital, Boston, MA
Inclusion body myositis (IBM) is a disease in which a particular type of T cells, CD8 T cells, invade muscle tissue and attacks it. This project proposes to develop a method to allow for visualizing the presence of these T cells in patients with IBM through x-ray scanning to determine which muscles these cells are invading and to what extent.

Phase I study of dalazatide in sporadic inclusion body myositis (2017)

Tahseen Mozaffar, MD
University of California, Irvine
Sporadic inclusion body myositis (sIBM), the most common adult acquired myopathy, causes substantial disability and has no effective treatment. Despite inflammation in the muscles, the disease does not respond to immunosuppressive drugs. Toxins derived from animal venoms have been found to selectively target a variety of autoimmune processes and have shown promise in animal models of multiple sclerosis and type 1 diabetes mellitus. Dalazatide, a drug derived from a toxin present in sea anemone, is being developed for autoimmune disease, with early phase studies in psoariasis. We plan to conduct a small pilot phase 1B study of dalazatide in ten subjects with sIBM over a six-month period to assess the safety and efficacy of this compound in sIBM.

Xenograft model of s-IBM (2016)

Thomas Lloyd, MD, PhD
Johns Hopkins University School of Medicine
The cause of sporadic inclusion body myositis (sIBM) is unknown. One major limitation to deciphering the etiology of sIBM is the lack of an animal model. The goal of this project is to generate a mouse model of sIBM by transplanting human muscle tissue from sIBM patients into immunodeficient mice. We will then use this model to study the disease in the absence of the human immune system to determine whether sIBM is caused by degeneration of the muscles or if it is the result of an autoimmune response. Furthermore, this project may provide the first clinically relevant mouse model of sporadic IBM. Such a model has the potential to be useful for future investigations into IBM including mechanistic studies and preclinical therapeutic testing.

Phenotypic, myopathologic, and biomarker correlation with NT5c1A seropositivity in sIBM patients: a prospective, multicenter, natural history study (2015)

Tahseen Mozaffar, MD
University of California, Irvine, CA
It is not known if the recently described presence of NT5c1A antibodies influences the disease presentation, disease course, and treatment responsiveness in inclusion-body myositis (IBM). This study investigates the differences in initial symptoms in IBM patients who test positive for this antibody versus those who test negative. It further evaluates the disease’s natural history over time and whether it progresses at a different rate in IBM patients who have the antibody versus those who don’t. Muscle pathology differences in the two groups will also be evaluated.

Hand function, activities of daily living and quality of life in patients with sIBM (2015)

Malin Regardt, PhD
Karolinska Institute, Stockholm, Sweden
Persons with sporatic inclusion-body myositis (sIBM) often have reduced hand function, which affects both their ability to perform daily activities as well as their quality of life. It is important for clinicians to consider such aspects of the disease that are of importance to patients. This project 1) tests an assessment tool for use in clinical practice; 2) tests a hand exercise program that may improve hand function, daily activities, and quality of life, and 3) investigates how the disease affects a patient’s ability to work.

Sequencing to identify novel therapeutic targets in sIBM (2013)

Conrad Weihl, MD, PhD
Washington University, St. Louis, MO
This study performed gene sequencing on 79 patients with well-documented sIBM. While no clear genetic cause or specific therapeutic target for sIBM was revealed, the results suggest that genetic evaluation in sIBM may nevertheless be clinically meaningful and lend insight into how symptoms arise.

Gene therapy in sIBM (2006, 2008, 2009)

Jerry Mendell, MD
Nationwide Children’s Hospital, Columbus, OH
This ongoing gene therapy trial used follistatin, a protein important in tissue rebuilding and repair, to encourage muscle cell growth in the treatment of muscle disease. Findings demonstrated increased muscle size and strength with reduced fibrosis in a genetically-modified mouse model of inclusion-body myositis (IBM) and subsequently in nonhuman primates. Continuing trials in IBM patients confirm the safety of this approach. This research has implications for other diseases of the muscles, including Becker muscular dystrophy.

Exploring a stem cell-based muscle regenerative therapy for IBM (2007)

Massimiliano Mirabella, MD, PhD
Institute of Neurology, Rome, Italy
This research studied inclusion-body myositis (IBM) mesoangioblasts, a class of adult stem cells associated with blood vessels that have therapeutic potential because of their ability to repair damaged and inflamed skeletal muscles. Researchers found that these stem cells also have the ability to modulate the immune system, suggesting that stem cell transplantation could benefit muscle inflammation and damage in IBM. Researchers have also identified a cytokine, a cell-signaling protein, that may represent a target for therapies aimed at increasing muscle regeneration.

The role of PAR-Y in pathogenesis and potential treatment of sIBM (2006)

Valerie Askanas, MD, PhD
University of Southern California Keck School of Medicine, Los Angeles, CA
Age-related changes in the muscle fiber may predispose the patient with inclusion-body myositis (IBM) to abnormalities in the mitochondria (the energy-generating parts of cells). This may provoke a vicious circle between mitochondrial malfunctions, cells’ ability to release toxins, and protein aggregation (a situation that causes cell damage). Researchers examined the mechanisms leading to the abnormal protein unfolding, misfolding, and aggregation within IBM muscle fibers and their presumed cytotoxic consequences. They predicted that improving the impaired protein disposal machinery and a better understanding of the mechanisms and consequences of human muscle fiber aging might provide new avenues for therapy in IBM.

Application of stance control orthosis in patients with IBM (2006)

Terry Oh, MD
Mayo Clinic, Rochester, MN
Inclusion-body myositis (IBM) affects both proximal and distal muscle groups with unique weakness patterns and quadriceps weakness. Falls due to knee buckling are common and are reported in 73% of people with IBM. Researchers studied gait patterns and applicability of new knee-ankle-foot stance control orthosis (SCO) in patients with IBM and gait instability. They found increasing gait abnormality with decreased strength of the quadriceps. Weakness of the quadriceps, however, was not the sole cause of the gait dysfunction; weakness in the adjacent muscles also seemed to play a role. This study showed that SCO use has potential benefits for IBM patients with knee extensor strength greater than 30-40% of the normal.

Use of exercise and dietary modification as treatments for IBM in a transgenic mouse model (2006)

Christa Studzinski, MD
University of Kentucky, Lexington, KY
The goal of this project was to study the role of diet and exercise in alleviating some of the symptoms (especially muscle wasting) of inclusion-body myositis (IBM). Using two different mouse models, researchers also looked at the efficacy of simple NSAIDs such as ibuprofen, naproxen, and others. Investigators found a modest benefit in the low-carb diet, although it didn’t significantly change the amyloid pathology associated with IBM. They found no benefit of NSAIDs on muscle function, but did find some alleviation of the amyloid pathology. This was a very promising finding, since the difficulty in treating amyloid pathology makes any treatment for IBM that addresses this pathology a welcome therapy.

Molecular pathogenesis of IBM (2005)

Hanns Lochmueller, MD
Friedrich Bauer Institute, Ludwig Maximilians University, Munich, Germany
Researchers examined disease mechanisms in inclusion-body myositis (IBM) at the molecular level. They classified muscle fibers from five patients with sporadic IBM as attacked or not attacked, and isolated the intracellular contents of muscle fibers separately through laser micro-dissection.

Role of myostatin in the pathogenesis and potential treatment of sIBM (2004)

Valerie Askanas, MD, PhD
University of Southern California Keck School of Medicine, Los Angeles, CA
Myostatin is a protein that limits muscle mass and strength. Based on biopsies from patients with inclusion-body myositis (IBM), researchers demonstrated that myostatin and a myostatin precursor accumulated within muscle fibers with amyloid beta. The study suggests that myostatin and myostatin precursor, either alone or bound to amyloid beta, may play a novel role in the disease-causing mechanisms of IBM.

Calcium dyshomeostasis and intramyofiber b-amyloid: Mechanisms of disease pathogenesis in IBM (2003)

Henry Querfurth, MD
Tufts-St. Elizabeth, Boston, MA
Deposits of amyloid beta are associated with muscle wasting in inclusion-body myositis (IBM). Previous reports have implicated dysregulation of amyloid beta precursor protein (betaAPP) expression and showed a tendency favoring fast-twitch fiber involvement in IBM, similar to misfolded protein deposition seen in other neurodegenerative diseases. Using genetically altered mice, researchers found increased levels of amyloid beta and a particular form of betaAPP in skeletal muscle fibers. These mice became significantly weaker with age compared with unaltered litter mates, and they exhibited typical myopathic features. Some muscle fibers from the genetically altered mice exhibited a two-fold increase in resting calcium and membrane depolarization compared with litter mates. These data indicate that over-expression of human betaAPP in fast-twitch skeletal muscle of transgenic mice leads to features characteristic of IBM. The increase in resting calcium and depolarization are novel findings, suggesting both a mechanism for the weakness and an avenue for therapeutic intervention in IBM.

The pathogenic role of excess cholesterol in sIBM muscle (2002)

Valerie Askanas, MD, PhD
University of Southern California Keck School of Medicine, Los Angeles, CA
This research identified several processes that play an important role in the development of inclusion-body myositis, including the abnormal accumulation of cholesterol.

The MHC processing and presentation machinery: clues for the immunopathogenesis of idiopathic inflammatory myopathies (2002)

Sabine Krause, MD, PhD
Friedrich Bauer Institute, Ludwig Maximilians University, Munich, Germany
This fellowship enabled the study of important aspects of surface molecules in skeletal muscle found in inflammatory myopathies and hereditary forms of inclusion-body myopathies.

Why are immune treatments not effective in IBM? (2004)

Jens Schmidt, MD
National Institutes of Health, Washington, DC
Despite the degeneration that inclusion-body myositis (IBM) shares with diseases such as Alzheimer’s dementia, there is a profound inflammation in IBM muscle. This study aims to understand why immune treatments such as steroids and immunoglobulins are not effective in IBM. It demonstrated that, in IBM patients treated with immunoglobulins or steroids, several mediators of inflammation were blocked or reduced, but the main cell stress parameters, including nitric oxide, remained unaltered. Novel agents that can reduce cell stress in skeletal muscle should be explored for their potential in IBM.