RARE DISEASE
Inclusion body myositis
Inclusion body myositis
Inclusion body myositis
Synonyms: IBM, Sporadic inclusion body myositis, sIBM
Synonyms: IBM, Sporadic inclusion body myositis, sIBM
Synonyms: IBM, Sporadic inclusion body myositis, sIBM
Drug discovery
7
drugs
With orphan designations
Overview
Inclusion Body Myositis (IBM) is a progressive inflammatory myopathy affecting individuals over 50, with a 3:1 male predominance. It causes asymmetric weakness in quadriceps, finger flexors, and swallowing muscles (dysphagia in ~50% of cases). Diagnosis requires clinical assessment, muscle biopsy (inflammatory infiltrates, rimmed vacuoles), and exclusion of mimics. IBM is refractory to immunosuppression and corticosteroids, with management focused on supportive therapies to maintain function [1][6][16].
Burden
Functional decline: 66% require assistive devices (canes, wheelchairs) within 10–15 years [6][15][16].
Healthcare costs: Annual median costs ~$44,838 (vs. $10,182 in controls), driven by rehab and complications [9].
Morbidity: Dysphagia increases aspiration risk; 20% have comorbid autoimmune conditions [5][10][20].
Therapies
Exercise/PT: Key for preserving strength; structured programs improve mobility and reduce falls [3][8][15].
Dysphagia management: Speech therapy and dietary modifications to prevent aspiration [3][6].
No disease-modifying treatments: Corticosteroids/immunosuppressants ineffective; IVIG shows transient benefit in limited cases [1][6][10].
Categories: rare neurological diseases, rare systemic and rheumatological diseases
Research Papers
513 drug discovery papers about Inclusion body myositis, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
513 drug discovery papers about Inclusion body myositis, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-04-07 | Autologous Fat-Derived Expanded Stem Cell Therapy as a Non-Surgical Approach for Musculoskeletal Conditions
Autologous fat-derived expanded mesenchymal stem cell therapy (MSCs) has been recognized as a significant non-surgical regenerative therapy for a variety of musculoskeletal and autoimmune diseases. Expanded MSCs have shown strong paracrine, anti-inflammatory, angiogenic, and immunomodulatory effects that can promote repair, pain relief, and possibly alter disease progression, especially when used early in the pathological process. Clinical experience with advanced imaging has shown that resolution of bone marrow oedema and subchondral cysts in knee osteoarthritis, regeneration of tendon structure in rotator cuff and Achilles tendinosis, fracture healing, and sustained functional results with MSC implantation can now be accomplished. The use of three-dimensional (3D) scaffolds of collagen and hyaluronic acid has now been shown to provide successful healing of extensive labral tears and paralabral cysts in hip disease. The intravenous route of delivery of expanded MSCs has also demonstrated a good safety profile with encouraging immunomodulatory effects in inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, inclusion body myositis, etc. The present chapter attempts to offer a clinical-academic synthesis of biological mechanisms, laboratory expansion methods, patient selection, delivery methods, imaging, and safety, which places autologous expanded MSC therapy as a developing concept of biologics for joint and tissue preservation.
2026-01-01 | Intravenous Autologous Adipose‑Derived Expanded Mesenchymal Stem Cell Therapy in Inclusion Body Myositis: A First‑in‑Human Case Report
Inclusion body myositis (IBM) is the most common acquired inflammatory myopathy in individuals over 50 years of age and remains refractory to conventional immunosuppressive and disease-modifying therapies. Its pathogenesis reflects a multifactorial process involving chronic cytotoxic T-cell–mediated inflammation, protein dyshomeostasis, mitochondrial dysfunction, and progressive muscle fiber degeneration. To date, human cell-based studies in IBM have been confined to localized intramuscular administration of adipose-derived mesenchymal stem cells, with no published reports describing systemic intravenous cell therapy.
2025-11-01 | Clonally expanded CD8 T cells recognize cryptic epitopes induced by TDP-43 pathology 3160
Abstract Description Aggregation of the RNA binding protein TDP-43 is a shared pathological feature in several neurodegenerative and inflammatory conditions. The resulting loss of function of TDP-43 leads to splicing defects and aberrant inclusion of cryptic exons (CEs), intronic sequences that are normally excluded from mRNA. While clonally expanded and highly differentiated CD8+ T cells have been observed to be particularly enriched in individuals with TDP-43 proteinopathies, their target antigens have remained elusive. In our work, we show that individuals with amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM) harbor clonally expanded populations of CD8+ T cells whose cognate epitopes are derived from CEs, particularly within HDGFL2 and IgLON5 proteins. We demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to CEs and are able to kill TDP-43 deficient cells. Finally, we identify a high expression of HDGFL2 cryptic peptide in IBM skeletal muscle, co-localized with TDP-43 pathology, alongside an enrichment of T cell and class I antigen presentation pathways. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking inflammation to TDP-43 pathology. Topic Categories Neuroimmunology (NEUR)
2025-06-27 | TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition
Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8+ T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8+ T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.
2025-02-13 | Emerging mechanisms and therapeutics in inflammatory muscle diseases.
Idiopathic inflammatory myopathies (IIMs), or myositis, are rare diseases marked by immune-driven muscle damage and complications like skin lesions and interstitial lung disease (ILD). Despite advances, challenges in diagnosis and treatment persist, particularly in inclusion body myositis (IBM), where no effective therapy exists. Recent breakthroughs, including transcriptomics and insights into antibody-mediated immunity and interferon (IFN) signaling, have clarified IIM pathophysiology and spurred the development of new therapies, such as chimeric antigen receptor (CAR) T cells and Janus kinase (JAK) inhibitors. We explore the latest findings on the mechanisms underlying adult-onset IIMs, emphasizing IBM pathobiology and its unique immune and degenerative pathways, such as a selective type 2 myofiber damage and severe cell stress. Finally, we highlight the recent advances in transcriptomics, single-cell analysis, and machine learning in transforming IIM research by improving diagnostic accuracy, uncovering therapeutic targets, and supporting the development of personalized treatment strategies.
antibodies
2026-06-09 | Phase II/III Study of Ulviprubart in Inclusion Body Myositis: Study Design, Patient Characteristics, and Topline Results (S7.007)
Describe the study design and results of a phase 2/3 study of ulviprubart for treatment of inclusion body myositis (IBM).
2025-11-11 | Case Report: Progressive interstitial lung disease secondary to Sjögren’s disease in a patient with inclusion body myositis complicated by dysphagia—a multidisciplinary approach and therapeutic challenges
We present the case of a 78-year-old man with a complex overlap of inclusion body myositis (IBM) and Sjögren’s disease (SjD), complicated by interstitial lung disease (ILD) and esophageal dysfunction. The patient’s neuromuscular decline was managed with periodic intravenous immunoglobulins (IVIG), while his progressive ILD required a combined immunosuppressive and antifibrotic regimen, including prednisone. This case underscores the diagnostic and therapeutic challenges in managing autoimmune overlap syndromes, particularly the rare coexistence of IBM and SjD-related ILD. We highlight the rationale behind the treatment strategy and the importance of a tailored, multidisciplinary approach in addressing both muscular and pulmonary manifestations.
2025-06-09 | LAG3 Is Expressed on Muscle-Infiltrating Cytotoxic T Cells, but Scarce on Circulating T Cells, in Patients With Inclusion Body Myositis.
Selective depletion of muscle-infiltrating pathogenic T cells is a promising therapeutic approach for inclusion body myositis (IBM), but no ideal cell surface antigen that is selectively expressed on these cells has been identified. LAG3 is expressed on highly differentiated, recently activated T cells, but detailed expression profiles in IBM patients have not been reported. This study was intended to bridge this research gap. First, biobank-stored skeletal muscle tissue samples (biceps or quadriceps) of six IBM patients, which had been biopsied for diagnosis, were used for immunohistochemistry (IHC) for T-cell antigens including LAG3 and CD244, a surface marker of late-differentiated lymphocytes. Next, eight IBM patients were enrolled, and fluorescence-activated cell sorting (FACS) was performed on their blood to count the LAG3-expressing cells. Muscle magnetic resonance imaging (MRI) and whole-blood microarrays were also performed. Upon analyzing LAG3 expression on 41-128 CD3+ lymphocytes and 11-86 CD244+ lymphocytes counted in the regions of interest (ROIs) for each biobank-stored sample, their positivity rates were 19.3%-48.0% and 41.7%-75.6%, respectively. In contrast, notably few LAG3-expressing cells were present in the blood. Both CD8+LAG3+ and CD8-LAG3+ cells constituted less than 0.1% of total T cells, although muscle MRI and blood microarray, showing upregulation of the proinflammatory genes GBP1 and GBP5, revealed both myositis and systemic inflammatory conditions in these patients. Agents that deplete LAG3+ lymphocytes, such as anti-LAG3 antibody that induces antibody-dependent cell cytotoxicity, are potential drug candidates with a favorable efficacy/safety balance for treating IBM.
2025-06-04 | Mitochondria-centred metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism.
To benchmark metabolomic signatures of inclusion body myositis (IBM) in muscle tissue, highlighting sex-specific differences and the correlation with clinical parameters. A total of 37 IBM patients and 22 controls without myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included disease duration and manual muscle test (MMT) scores. Discovery metabolite screening and quantitative targeted metabolomics platforms were used. Levels of metabolites and RNA-metabolomic integrated modules were correlated with clinical parameters and the mitophagy marker, p-S65-Ubiquitin (p-S65-Ub). IBM muscle samples showed elevated citric acid (TCA) cycle intermediates and anaplerotic amino acids. Proximal glycolytic intermediates were decreased, while pentose phosphate pathway (PPP) metabolites were increased. Short-chain acylcarnitines were lower in IBM males but not in females. Lastly, nucleic acid bases were increased, and nucleotides were decreased. MMT correlated with PPP metabolites and nucleic acid bases, and inversely correlated with glycolysis metabolites and mono/diphosphate nucleotides. MMT also correlated with several amino acids, including cysteine, taurine, carnosine, and sarcosine. Acylcarnitines correlated with disease duration only in males. Four RNA-metabolomic integrated modules demonstrated significant correlations. The strongest correlations were observed between the pink module and both sexes and p-S65-Ub. MMT and p-S65-Ub correlated with 3 and 2 modules, respectively. The enriched pathways were related to central carbon metabolism, cytokine/chemokine signalling, neurotransmission, and mitogen-activated protein kinase (MAPK)/RAS signalling. Males had relatively similar correlations to the combined-sex analysis, while females had no significant correlation with any module. IBM is associated with clinically significant alterations in central carbon metabolism, with the strongest RNA-metabolomic-clinical correlations observed in males. Further research is needed to explore the role of these metabolic changes in IBM pathogenesis and their progression over time.
2025-06-01 | POS1063 ULVIPRUBART PHARMACOKINETICS, PHARMACODYNAMICS (PK/PD), AND SAFETY: PHASE 1 STUDY RESULTS IN PATIENTS WITH INCLUSION BODY MYOSITIS (IBM)
IBM is a rare, progressive disease characterized by invasion of muscle by highly differentiated cytotoxic CD8+ T cells. Ulviprubart, a monoclonal antibody, selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting KLRG1 expressed on most IBM-muscle–infiltrating T cells. Here, we describe PK/PD and safety of ulviprubart in patients with IBM. In this phase 1, open-label study (NCT04659031), initial patients received subcutaneous ulviprubart (0.1, 0.5, or 2.0 mg/kg) as a single dose prior to dosing every 8 weeks (Q8W) ~6−12 months later, while later patients received 2.0 mg/kg Q8W; patients received ulviprubart for up to 18 months. PK/PD and safety with ulviprubart were assessed. Nineteen patients (mean age, 66 years; 79% male) were enrolled (0.1 mg/kg: n=3; 0.5 mg/kg: n=3; 2.0 mg/kg: n=13). Ulviprubart displayed a long absorption phase, slow clearance, and 21-day half-life. Peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T cell depletion was achieved, with mean CD8+ KLRG1+ T cell maximum depletions of 69%, 97%, and 98% after single doses of 0.1, 0.5, and 2.0 mg/kg, respectively. Effector CD8+ T cell populations (T-cell effector memory [TEM] and TEMs expressing CD45RA [TEMRA]) were depleted to the extent of their KLRG1 expression. Regulatory T cells and B cells were preserved. No serious adverse events (AEs) or discontinuations due to AEs were reported. In patients with IBM, ulviprubart led to sustained selective depletion of peripheral blood CD8+ KLRG1+ T cells and had a favorable safety profile. NIL. This study is sponsored by Abcuro, Inc. Merrilee Needham Abcuro, Inc. − Consultant, Robert D. Henderson Abcuro, Inc. − Consultant, Christina Liang Abcuro, Inc. − Consultant, Dulce Soler-Ferran Abcuro, Inc. – Employment, H. Jeffrey Wilkins Abcuro, Inc. – Employment, Steven A. Greenberg Abcuro, Inc. – Founder, Abcuro, Inc. – Consultant. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
proteins
2026-08-13 | Sporadic inclusion body myositis: overreliance on histology may lead to misdiagnosis
Abstract We describe a 57-year-old man who had initial isolated weakness in the deep finger flexors of his non-dominant hand, followed by quadriceps weakness and wasting a year later. Despite the distribution specific for sporadic inclusion body myositis (s-IBM) and early myogenic abnormalities found in deep finger flexors, the case was initially misdiagnosed as polymyositis based on the initial biopsy results, which revealed endomysial inflammation with partial invasion/compression of non-necrotic fiber, without rimmed vacuoles. As a result, the patient received unnecessary treatment, including immunosuppressants, which caused serious side effects. The second biopsy revealed rimmed vacuoles, and the diagnosis of s-IBM was confirmed. The role of clinical, pathological, and electrophysiological features for early diagnosis of s-IBM and differentiation from PM is discussed.
2026-03-24 | Anti-signal recognition particle antibody-positive immune-mediated necrotising myopathy with inclusion body myositis-like features in a patient with human immunodeficiency virus and syphilis infection.
Inclusion body myositis (IBM) and immune-mediated necrotising myopathy (IMNM) are inflammatory myopathies characterized by specific clinical and pathological features. IBM is associated with human immunodeficiency virus (HIV) infection, whereas IMNM is extremely rare in individuals positive for HIV. To date, no reports have described the coexistence of IMNM and IBM-like pathological features in patients positive for HIV. Herein, we report a rare case of a 40-year-old man with HIV-associated subacute progressive myopathy presenting with simultaneous proximal and distal muscle weakness, dysphagia, and markedly elevated creatine kinase levels. Serological testing revealed strong positivity for anti-signal recognition particle antibodies. Muscle biopsy revealed coexisting pathological features suggesting both IMNM and IBM. The patient showed insufficient response to antiretroviral therapy and glucocorticoids; however, intravenous immunoglobulin therapy resulted in a marked clinical response. This case highlights the possible coexistence of IMNM and IBM-like pathology in the context of HIV infection and provides insights into the pathophysiology of HIV-associated myopathy. Furthermore, this report suggests the potential effectiveness of intravenous immunoglobulin treatment in such cases.
2025-06-26 | Mitochondrial pathology in inflammatory myopathies: a marker of worse clinical outcome.
Mitochondrial dysfunction is well documented in inclusion body myositis (IBM), but its role in non-IBM myositis remains unclear. This study aimed to investigate the prevalence and clinical significance of mitochondrial pathology in non-IBM myositis and to assess its potential role as a marker for disease progression towards IBM, treatment response, and clinical outcomes. Muscle biopsies from 850 patients with inflammatory myopathy (IM) across 6 neuromuscular centers in Italy, France, and Germany were retrospectively analyzed. Inclusion required meeting diagnostic criteria for definite adult IM, mitochondrial pathology (age-exceeding numbers of COX-negative fibers), and exclusion of definite IBM according to Hilton-Jones 2013 criteria. The percentage of COX-negative fibers was quantified, correlated with clinical outcomes, and compared with myositis control cases without relevant signs of mitochondrial alterations. Twenty-five patients with non-IBM myositis and mitochondrial abnormalities were identified. These patients, predominantly women (68%), had a mean onset age of 58.8 years. Polymyositis with mitochondrial pathology (PM-Mito) and nonspecific myositis (NSM) were the most prevalent subtypes (72%). The mean percentage of COX-negative fibers was 3% (0.25-8.5%) in these patients. The presence of mitochondrial pathology was associated with treatment refractoriness and worse clinical outcome evaluated based on residual muscle weakness and the level of independence (p < 0.005). A higher percentage of COX-negative fibers also correlated with poorer clinical outcomes (p = 0.031). Four patients, initially diagnosed with PM-Mito and NSM, progressed to definite IBM. Mitochondrial dysfunction represents a key element informing about disease severity and poor clinical outcomes in non-IBM myositis. It may predict progression to IBM, especially in PM-Mito and NSM, and guide treatment strategies.
2022-07-20 | Botulinum toxin treatment improves dysphagia in patients with oculopharyngeal muscular dystrophy and sporadic inclusion body myositis.
Dysphagia can be troublesome in sporadic inclusion body myositis (sIBM) and oculopharyngeal muscular dystrophy (OPMD), but no established treatment exists. Cricopharyngeal muscle botulinum toxin injection has at case level been reported to be effective. We evaluated safety and efficacy of botulinum toxin injections in the cricopharyngeal muscle in patients with dysphagia due to sIBM or OPMD. Participants were included from our outpatient clinic. Cricopharyngeal constriction was confirmed by laryngoscopy. After EMG confirmation of needle placement in the cricopharyngeal muscle, botulinum toxin A was injected in awake patients. An individualized dose of 5-10 units of botulinum toxin A was applied initially and titrated up a maximum of 3 times. Outcome measures were change in dysphagia questionnaire, timed cold-water swallow test and subjective dysphagia status (worse, unchanged, improved). Due to the need for individualized dosing and a limited number of available patients, an uncontrolled, un-blinded design was used. Thirteen patients, 3 with OPMD, received at least 1 injection. In the dysphagia questionnaire, all but 2 subjects, none with subjective worsening, improved (p < 0.001). Subjectively, seven felt an improvement, 4 no change and 2 a worsening. No overall change was seen the timed cold-water swallow test. No serious adverse events were observed. Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods. EudraCT-number: 2014-002210-23.
2022-07-12 | Inclusion Body Myositis and Neoplasia: A Narrative Review.
Inclusion body myositis (IBM) is an acquired, late-onset inflammatory myopathy, with both inflammatory and degenerative pathogenesis. Although idiopathic inflammatory myopathies may be associated with malignancies, IBM is generally not considered paraneoplastic. Many studies of malignancy in inflammatory myopathies did not include IBM patients. Indeed, IBM is often diagnosed only after around 5 years from onset, while paraneoplastic myositis is generally defined as the co-occurrence of malignancy and myopathy within 1 to 3 years of each other. Nevertheless, a significant association with large granular lymphocyte leukemia has been recently described in IBM, and there are reports of cancer-associated IBM. We review the pathogenic mechanisms supposed to be involved in IBM and outline the common mechanisms in IBM and malignancy, as well as the therapeutic perspectives. The terminally differentiated, CD8+ highly cytotoxic T cells expressing NK features are central in the pathogenesis of IBM and, paradoxically, play a role in some cancers as well. Interferon gamma plays a central role, mostly during the early stages of the disease. The secondary mitochondrial dysfunction, the autophagy and cell cycle dysregulation, and the crosstalk between metabolic and mitogenic pathways could be shared by IBM and cancer. There are intermingled subcellular mechanisms in IBM and neoplasia, and probably their co-existence is underestimated. The link between IBM and cancers deserves further interest, in order to search for efficient therapies in IBM and to improve muscle function, life quality, and survival in both diseases.
small molecules
2026-05-27 | Idiopathic Inflammatory Myopathies-Treatment Perspective of Highly Specialised Rheumatology Centre.
Background/Objectives: Idiopathic inflammatory myopathies (IIMs) are chronic immune-mediated disorders, causing striated muscle weakness and extramuscular symptoms. Real-world, single-centre data are needed to interpret phenotype patterns and evolving therapies. Methods: A single-centre, retrospective cohort study was conducted at the Rheumatology Clinic of the National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland from 1 January 2022 to 31 December 2025. Data included demographics, IIM subtypes, extramuscular involvement, co-existing Sjögren disease (SD), biopsy results, autoantibodies, and treatment. Due to sample size, descriptive analysis was used. Results: The study included 35 patients (31.4% men). Mean age was 50.7 years; mean body mass index (BMI) was 26.0 kg/m2. The cohort consisted of 10 dermatomyositis (DM), one polymyositis (PM), two immune-mediated necrotising myopathy (IMNM), one inclusion body myositis (IBM), 16 anti-synthetase syndrome (ASyS), four juvenile dermatomyositis (JDM), and one clinically amyopathic dermatomyositis (CADM). SD co-occurred in eight cases, including six cases of ASyS. Anti-Jo1 was observed in 13 ASyS cases and one DM. Glucocorticoids (GCSs) were administered in all patients for induction in addition to cyclophosphamide (28.6%), mycophenolate mofetil (MMF) (51.4%), and methotrexate (MTX) (17.1%). Maintenance therapy included MTX (20%), MMF (31.4%), rituximab (34.3%), azathioprine (AZA) (42.9%), and others. Two DM, two JDM, and one ASyS patient received JAK inhibitors, one DM and one JDM anifrolumab, one IBM sirolimus, and four patients with interstitial lung disease (ILD) nintedanib. Conclusions: This Polish single-centre cohort shows effective use of novel therapies for IIM. Sirolimus, JAK inhibitors, and nintedanib were effective. Co-occurrence of SD in ASyS patients requires further research.
2026-03-15 | Modifying muscle metabolic dysregulation in inclusion body myositis with pioglitazone: a single-arm trial.
This single-arm, open-label phase 1 trial evaluated the PPARγ agonist pioglitazone in patients with inclusion body myositis (IBM). After a 16-week observation (lead-in) period, participants received pioglitazone 45 mg daily for 32 weeks. The primary outcome was the change in PPARGC1A expression and related metabolic pathways in muscle after 16 weeks of treatment compared with the lead-in period. Of the 16 enrolled participants, 13 initiated pioglitazone and completed at least one on-treatment assessment; the trial was terminated early due to the COVID-19 pandemic. At baseline, muscle metabolomics revealed broad metabolic abnormalities compared with controls. Pioglitazone reversed elements of this signature, increasing PPARGC1A expression (p = 0.099) and modulating downstream pathways in muscle, including enhanced oxidative phosphorylation. Clinical outcomes were unchanged overall, but a subset with favorable metabolic responses showed slower decline in the IBM-Functional Rating Score (IBM-FRS) and Modified Timed Up and Go (m-TUG). Reported adverse effects included myalgia and heart failure exacerbation. As a phase 1 trial with a limited cohort, these findings provide preliminary evidence that pioglitazone modulates muscle metabolism and warrants further investigation in IBM. This study was supported by the Ira T. Discovery Fund and the Peter and Carmen Lucia Buck Foundation Myositis Discovery Fund. Clinical Trials Registration: NCT03440034.
2026-02-27 | Multilevel impairment of mitochondrial respiration with sex-specific signatures in inclusion body myositis.
Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary tests from RNA level to high-resolution respirometry on permeabilized muscle fibers was performed. The relationship between respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine the clinical significance of the findings. The study included a total of 67 patients with IBM and 45 controls. IBM muscle tissue exhibited reduced maximal respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, males had decreased State 3 intrinsic respiration, whereas females had greater intrinsic respiration in leak states. Complex II control ratio strongly correlated with disease duration and severity only in females. IBM was associated with decreased RNA and protein expression of OXPHOS complexes. Complex I activity was decreased mainly in females. IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that correlated with disease duration in females. In IBM, there was decreased mtDNA content, and impaired mitophagy, both of which strongly correlated with respirometry measures and markers of disease severity, indicating these pathways are likely interconnected and of clinical significance. IBM is characterized by multilevel impairments in mitochondrial coupling efficiency, revealing several potential therapeutic targets to improve mitochondrial fitness, while accounting for sex-specific differences.
2025-11-26 | PO:25:082 | Progressive interstitial lung disease secondary to Sjögren's disease in a patient with inclusion body myositis complicated by dysphagia: a multidisciplinary approach and therapeutic challenges
Background. Inclusion Body Myositis (IBM) is a rare idiopathic inflammatory myopathy, characterized by an insidious onset with progressive muscle weakness and dysphagia. While its association with Sjögren’s syndrome (pSS) has been reported, this overlap is uncommon and often challenging to manage. We present the case of a patient affected by this dual condition, treated at our center. Case report. A 70-year-old man, a former smoker, with a medical history of hypertension, hypothyroidism, transient ischemic attack, and prior intestinal obstruction surgery, presented to rheumatologic evaluation in 2017 with progressive dysphagia and muscle weakness. A diagnosis of IBM was established and confirmed by muscle biopsy. The patient was subsequently treated with intravenous immunoglobulins and pyridostigmine, achieving clinical improvement. In 2023, the patient developed new-onset xerophthalmia, xerostomia, and progressive exertional dyspnea. The comprehensive diagnostic work-up included a chest CT scan showing subpleural reticular thickening, mainly in the posterior-basal segments of the lower lobes, in the lateral segments of the middle lobe, and in the superior segments of the lingula. Pulmonary function testing showed a restrictive ventilatory defect and a moderate drop in DLCO. Serological analysis showed anti-Ro52 antibody positivity, and minor salivary gland biopsy demonstrated a focus score of 1. The overall findings were consistent with pSS. In 2024, due to worsening dyspnea, a new chest CT was performed, showing disease progression with the appearance of pulmonary fibrosis (radiologic UIP pattern). The case was discussed during a multidisciplinary meeting involving radiologists, pulmonologists, and rheumatologists. Due to the clinical and radiological deterioration of pSS-associated interstitial lung disease, treatment with nintedanib 150 mg twice daily, prednisone 50 mg with gradual tapering, and cyclophosphamide according to the NIH protocol was initiated. Maintenance therapy with mycophenolate mofetil 2 g/day was subsequently introduced. At follow-up spirometry, pulmonary function remained stable, although CT imaging showed mild disease progression with increased bronchiectasis. The patient’s clinical and therapeutic management is ongoing under multidisciplinary follow-up. Conclusions. This case highlights two key aspects: the intrinsic complexity in managing inclusion body myositis associated with pSS, and the essential role of a multidisciplinary approach in defining not only the initial treatment but also subsequent therapeutic adjustments based on clinical and instrumental evolution. Furthermore, the combination of an immunosuppressive drug with an antifibrotic agent may represent an effective therapeutic strategy to achieve clinical, radiological, and functional stabilization of interstitial lung disease in patients with pSS.
2025-10-30 | Emerging Treatment Options for Inclusion Body Myositis.
Inclusion body myositis (IBM) is a disabling and progressive muscle disease with no effective disease-modifying therapies. This article summarizes recent advances in IBM therapeutics, analysing the reasons for historic trial failures and highlighting more promising contemporary approaches. Improved understanding of IBM's multifaceted pathogenesis has led to development of targeted approaches-including agents modulating autophagy, myostatin inhibition, and T-cell dysregulation. In addition to pharmacologic interventions, exercise-based strategies, robotics, and surgical procedures are being explored for symptom management. Dysphagia, a major contributor to morbidity, is receiving increased attention through both conservative and interventional approaches.
other
2026-07-09 | AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.
Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.
2026-06-02 | Genetic Variation in Follistatin and its Role in Muscle Recovery and Hypertrophy: A Dose-Dependent Mechanistic Review
The Follistatin (FST)--Myostatin axis is a primary regulator of skeletalmuscle plasticity, governing both hypertrophy and regenerative capacity. Whilethe anabolic potential of Follistatin overexpression is well-established, thespecific signaling consequences of graded, physiological perturbations (such asthose arising from natural genetic variation or titrated gene therapies) remainunderexplored. This review synthesizes current literature to distinguish betweenthe effects of binary overexpression versus dose-dependent modulation ofFollistatin. We examine the dual mechanisms of FST action: the canonicalsuppression of Smad2/3 signaling via Myostatin/Activin blockade and thecooperative activation of the Akt/mTOR/S6K pathway through obligate IGF-Ireceptor co-signaling. Emerging evidence from human FST polymorphism studiesdemonstrates that naturally occurring variation in the FST locus tonicallymodulates muscle mass and exercise adaptability across the lifespan. Inparallel, phase 1/2a gene therapy trials show that AAV-mediated FST deliveryproduces measurable functional gains in patients with Becker muscular dystrophyand sporadic inclusion body myositis. The same ligand promiscuity that makesFST potent also renders it hazardous in excess: supraphysiological levelssuppress FSH secretion, impair reproductive function, and, through inadvertentGDF11 inhibition, compromise bone integrity. We conclude that future researchmust map the graded dose--response landscape of FST to define the therapeuticwindow for muscle recovery and hypertrophy while avoiding systemic off-targettoxicity.
2025-12-08 | Antisense oligonucleotides targeting valosin-containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.
Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease presents with variable combinations of inclusion body myopathy, early-onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology. In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5 µM and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39-56]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanised VCP severe A232E pathogenic gene variant (VCP A232E mice) with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95% CI [27-32]) knockdown of VCP protein compared with control ASO. The ASO-mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TAR DNA binding protein 43 (TDP-43) expression, hallmarks of VCP related MSP1. In addition, ASO-treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared with mice treated with control ASO. These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP related MSP1. VCP multisystem proteinopathy 1 is caused by gain-of-function pathogenic variants of the VCP gene. VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). The ASOs reduced VCP, TDP-43, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.
2025-11-19 | Murine toxicology assessment of avgn7.2, a novel gene therapeutic for inclusion body myositis and other muscle wasting diseases.
Sporadic inclusion body myositis (IBM) is a highly debilitating muscle degenerative and rare disease of the middle aged and elderly. Because immunosuppressants fail to prevent muscle wasting in IBM patients and can even exacerbate it, drugs like AVGN7.2 are being developed to halt degeneration and to enhance muscle mass and function. AVGN7.2 is a novel gene therapeutic that attenuates activin receptors through muscle-specific human (h) SMAD7 expression and as part of its preclinical development, we performed a 91-day single-dose toxicology assessment of systemic safety, biodistribution and immunogenicity in accordance with Good Laboratory Practices. Standard physiological, ophthalmoscopic, hematological and serum chemistry examinations were performed and no adverse drug-related effects were detected at any dose (2.3E + 13, 7E + 13 and 2.1E + 14 vg/kg), resulting in a No Observed Adverse Effect Level of 2.1e14 vg/kg. Mice mounted early IgM and late IgG responses to the AAV6 capsid, but no response to the hSMAD7 protein. Vector biodistribution mirrored previously published patterns with liver followed by striated muscle having the highest levels, although overexpression of hSMAD7 and the S6RP biomarker only occurred in muscle. These data suggest that AVGN7.2 was well-tolerated even at doses known to elicit clinical toxicities with muscle-tropic AAV capsids other than AAV6.
2010-07-09 | Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress.
Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. Its muscle-fiber phenotype shares several molecular similarities with Alzheimer-disease (AD) brain, including increased AbetaPP, accumulation of amyloid-beta (Abeta), and increased BACE1 protein. Abeta42 is prominently increased in AD brain and within s-IBM fibers, and its oligomers are putatively toxic to both tissues--accordingly, minimizing Abeta42 production can be a therapeutic objective in both tissues. The pathogenic development of s-IBM is unknown, including the mechanisms of BACE1 protein increase. BACE1 is an enzyme essential for production from AbetaPP of Abeta42 and Abeta40, which are proposed to be detrimental within s-IBM muscle fibers. Novel noncoding BACE1-antisense (BACE1-AS) was recently shown (a) to be increased in AD brain, and (b) to increase BACE1 mRNA and BACE1 protein. We studied BACE1-AS and BACE1 transcripts by real-time PCR (a) in 10 s-IBM and 10 age-matched normal muscle biopsies; and (b) in our established ER-Stress-Human-Muscle-Culture-IBM Model, in which we previously demonstrated increased BACE1 protein. Our study demonstrated for the first time that (a) in s-IBM biopsies BACE1-AS and BACE1 transcripts were significantly increased, suggesting that their increased expression can be responsible for the increase of BACE1 protein; and (b) experimental induction of ER stress significantly increased both BACE1-AS and BACE1 transcripts, suggesting that ER stress can participate in their induction in s-IBM muscle. Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1.
cell therapies
2026-04-07 | Autologous Fat-Derived Expanded Stem Cell Therapy as a Non-Surgical Approach for Musculoskeletal Conditions
Autologous fat-derived expanded mesenchymal stem cell therapy (MSCs) has been recognized as a significant non-surgical regenerative therapy for a variety of musculoskeletal and autoimmune diseases. Expanded MSCs have shown strong paracrine, anti-inflammatory, angiogenic, and immunomodulatory effects that can promote repair, pain relief, and possibly alter disease progression, especially when used early in the pathological process. Clinical experience with advanced imaging has shown that resolution of bone marrow oedema and subchondral cysts in knee osteoarthritis, regeneration of tendon structure in rotator cuff and Achilles tendinosis, fracture healing, and sustained functional results with MSC implantation can now be accomplished. The use of three-dimensional (3D) scaffolds of collagen and hyaluronic acid has now been shown to provide successful healing of extensive labral tears and paralabral cysts in hip disease. The intravenous route of delivery of expanded MSCs has also demonstrated a good safety profile with encouraging immunomodulatory effects in inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, inclusion body myositis, etc. The present chapter attempts to offer a clinical-academic synthesis of biological mechanisms, laboratory expansion methods, patient selection, delivery methods, imaging, and safety, which places autologous expanded MSC therapy as a developing concept of biologics for joint and tissue preservation.
2026-01-01 | Intravenous Autologous Adipose‑Derived Expanded Mesenchymal Stem Cell Therapy in Inclusion Body Myositis: A First‑in‑Human Case Report
Inclusion body myositis (IBM) is the most common acquired inflammatory myopathy in individuals over 50 years of age and remains refractory to conventional immunosuppressive and disease-modifying therapies. Its pathogenesis reflects a multifactorial process involving chronic cytotoxic T-cell–mediated inflammation, protein dyshomeostasis, mitochondrial dysfunction, and progressive muscle fiber degeneration. To date, human cell-based studies in IBM have been confined to localized intramuscular administration of adipose-derived mesenchymal stem cells, with no published reports describing systemic intravenous cell therapy.
2025-11-01 | Clonally expanded CD8 T cells recognize cryptic epitopes induced by TDP-43 pathology 3160
Abstract Description Aggregation of the RNA binding protein TDP-43 is a shared pathological feature in several neurodegenerative and inflammatory conditions. The resulting loss of function of TDP-43 leads to splicing defects and aberrant inclusion of cryptic exons (CEs), intronic sequences that are normally excluded from mRNA. While clonally expanded and highly differentiated CD8+ T cells have been observed to be particularly enriched in individuals with TDP-43 proteinopathies, their target antigens have remained elusive. In our work, we show that individuals with amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM) harbor clonally expanded populations of CD8+ T cells whose cognate epitopes are derived from CEs, particularly within HDGFL2 and IgLON5 proteins. We demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to CEs and are able to kill TDP-43 deficient cells. Finally, we identify a high expression of HDGFL2 cryptic peptide in IBM skeletal muscle, co-localized with TDP-43 pathology, alongside an enrichment of T cell and class I antigen presentation pathways. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking inflammation to TDP-43 pathology. Topic Categories Neuroimmunology (NEUR)
2025-06-27 | TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition
Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8+ T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8+ T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.
2025-02-13 | Emerging mechanisms and therapeutics in inflammatory muscle diseases.
Idiopathic inflammatory myopathies (IIMs), or myositis, are rare diseases marked by immune-driven muscle damage and complications like skin lesions and interstitial lung disease (ILD). Despite advances, challenges in diagnosis and treatment persist, particularly in inclusion body myositis (IBM), where no effective therapy exists. Recent breakthroughs, including transcriptomics and insights into antibody-mediated immunity and interferon (IFN) signaling, have clarified IIM pathophysiology and spurred the development of new therapies, such as chimeric antigen receptor (CAR) T cells and Janus kinase (JAK) inhibitors. We explore the latest findings on the mechanisms underlying adult-onset IIMs, emphasizing IBM pathobiology and its unique immune and degenerative pathways, such as a selective type 2 myofiber damage and severe cell stress. Finally, we highlight the recent advances in transcriptomics, single-cell analysis, and machine learning in transforming IIM research by improving diagnostic accuracy, uncovering therapeutic targets, and supporting the development of personalized treatment strategies.
antibodies
2026-06-09 | Phase II/III Study of Ulviprubart in Inclusion Body Myositis: Study Design, Patient Characteristics, and Topline Results (S7.007)
Describe the study design and results of a phase 2/3 study of ulviprubart for treatment of inclusion body myositis (IBM).
2025-11-11 | Case Report: Progressive interstitial lung disease secondary to Sjögren’s disease in a patient with inclusion body myositis complicated by dysphagia—a multidisciplinary approach and therapeutic challenges
We present the case of a 78-year-old man with a complex overlap of inclusion body myositis (IBM) and Sjögren’s disease (SjD), complicated by interstitial lung disease (ILD) and esophageal dysfunction. The patient’s neuromuscular decline was managed with periodic intravenous immunoglobulins (IVIG), while his progressive ILD required a combined immunosuppressive and antifibrotic regimen, including prednisone. This case underscores the diagnostic and therapeutic challenges in managing autoimmune overlap syndromes, particularly the rare coexistence of IBM and SjD-related ILD. We highlight the rationale behind the treatment strategy and the importance of a tailored, multidisciplinary approach in addressing both muscular and pulmonary manifestations.
2025-06-09 | LAG3 Is Expressed on Muscle-Infiltrating Cytotoxic T Cells, but Scarce on Circulating T Cells, in Patients With Inclusion Body Myositis.
Selective depletion of muscle-infiltrating pathogenic T cells is a promising therapeutic approach for inclusion body myositis (IBM), but no ideal cell surface antigen that is selectively expressed on these cells has been identified. LAG3 is expressed on highly differentiated, recently activated T cells, but detailed expression profiles in IBM patients have not been reported. This study was intended to bridge this research gap. First, biobank-stored skeletal muscle tissue samples (biceps or quadriceps) of six IBM patients, which had been biopsied for diagnosis, were used for immunohistochemistry (IHC) for T-cell antigens including LAG3 and CD244, a surface marker of late-differentiated lymphocytes. Next, eight IBM patients were enrolled, and fluorescence-activated cell sorting (FACS) was performed on their blood to count the LAG3-expressing cells. Muscle magnetic resonance imaging (MRI) and whole-blood microarrays were also performed. Upon analyzing LAG3 expression on 41-128 CD3+ lymphocytes and 11-86 CD244+ lymphocytes counted in the regions of interest (ROIs) for each biobank-stored sample, their positivity rates were 19.3%-48.0% and 41.7%-75.6%, respectively. In contrast, notably few LAG3-expressing cells were present in the blood. Both CD8+LAG3+ and CD8-LAG3+ cells constituted less than 0.1% of total T cells, although muscle MRI and blood microarray, showing upregulation of the proinflammatory genes GBP1 and GBP5, revealed both myositis and systemic inflammatory conditions in these patients. Agents that deplete LAG3+ lymphocytes, such as anti-LAG3 antibody that induces antibody-dependent cell cytotoxicity, are potential drug candidates with a favorable efficacy/safety balance for treating IBM.
2025-06-04 | Mitochondria-centred metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism.
To benchmark metabolomic signatures of inclusion body myositis (IBM) in muscle tissue, highlighting sex-specific differences and the correlation with clinical parameters. A total of 37 IBM patients and 22 controls without myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included disease duration and manual muscle test (MMT) scores. Discovery metabolite screening and quantitative targeted metabolomics platforms were used. Levels of metabolites and RNA-metabolomic integrated modules were correlated with clinical parameters and the mitophagy marker, p-S65-Ubiquitin (p-S65-Ub). IBM muscle samples showed elevated citric acid (TCA) cycle intermediates and anaplerotic amino acids. Proximal glycolytic intermediates were decreased, while pentose phosphate pathway (PPP) metabolites were increased. Short-chain acylcarnitines were lower in IBM males but not in females. Lastly, nucleic acid bases were increased, and nucleotides were decreased. MMT correlated with PPP metabolites and nucleic acid bases, and inversely correlated with glycolysis metabolites and mono/diphosphate nucleotides. MMT also correlated with several amino acids, including cysteine, taurine, carnosine, and sarcosine. Acylcarnitines correlated with disease duration only in males. Four RNA-metabolomic integrated modules demonstrated significant correlations. The strongest correlations were observed between the pink module and both sexes and p-S65-Ub. MMT and p-S65-Ub correlated with 3 and 2 modules, respectively. The enriched pathways were related to central carbon metabolism, cytokine/chemokine signalling, neurotransmission, and mitogen-activated protein kinase (MAPK)/RAS signalling. Males had relatively similar correlations to the combined-sex analysis, while females had no significant correlation with any module. IBM is associated with clinically significant alterations in central carbon metabolism, with the strongest RNA-metabolomic-clinical correlations observed in males. Further research is needed to explore the role of these metabolic changes in IBM pathogenesis and their progression over time.
2025-06-01 | POS1063 ULVIPRUBART PHARMACOKINETICS, PHARMACODYNAMICS (PK/PD), AND SAFETY: PHASE 1 STUDY RESULTS IN PATIENTS WITH INCLUSION BODY MYOSITIS (IBM)
IBM is a rare, progressive disease characterized by invasion of muscle by highly differentiated cytotoxic CD8+ T cells. Ulviprubart, a monoclonal antibody, selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting KLRG1 expressed on most IBM-muscle–infiltrating T cells. Here, we describe PK/PD and safety of ulviprubart in patients with IBM. In this phase 1, open-label study (NCT04659031), initial patients received subcutaneous ulviprubart (0.1, 0.5, or 2.0 mg/kg) as a single dose prior to dosing every 8 weeks (Q8W) ~6−12 months later, while later patients received 2.0 mg/kg Q8W; patients received ulviprubart for up to 18 months. PK/PD and safety with ulviprubart were assessed. Nineteen patients (mean age, 66 years; 79% male) were enrolled (0.1 mg/kg: n=3; 0.5 mg/kg: n=3; 2.0 mg/kg: n=13). Ulviprubart displayed a long absorption phase, slow clearance, and 21-day half-life. Peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T cell depletion was achieved, with mean CD8+ KLRG1+ T cell maximum depletions of 69%, 97%, and 98% after single doses of 0.1, 0.5, and 2.0 mg/kg, respectively. Effector CD8+ T cell populations (T-cell effector memory [TEM] and TEMs expressing CD45RA [TEMRA]) were depleted to the extent of their KLRG1 expression. Regulatory T cells and B cells were preserved. No serious adverse events (AEs) or discontinuations due to AEs were reported. In patients with IBM, ulviprubart led to sustained selective depletion of peripheral blood CD8+ KLRG1+ T cells and had a favorable safety profile. NIL. This study is sponsored by Abcuro, Inc. Merrilee Needham Abcuro, Inc. − Consultant, Robert D. Henderson Abcuro, Inc. − Consultant, Christina Liang Abcuro, Inc. − Consultant, Dulce Soler-Ferran Abcuro, Inc. – Employment, H. Jeffrey Wilkins Abcuro, Inc. – Employment, Steven A. Greenberg Abcuro, Inc. – Founder, Abcuro, Inc. – Consultant. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
proteins
2026-08-13 | Sporadic inclusion body myositis: overreliance on histology may lead to misdiagnosis
Abstract We describe a 57-year-old man who had initial isolated weakness in the deep finger flexors of his non-dominant hand, followed by quadriceps weakness and wasting a year later. Despite the distribution specific for sporadic inclusion body myositis (s-IBM) and early myogenic abnormalities found in deep finger flexors, the case was initially misdiagnosed as polymyositis based on the initial biopsy results, which revealed endomysial inflammation with partial invasion/compression of non-necrotic fiber, without rimmed vacuoles. As a result, the patient received unnecessary treatment, including immunosuppressants, which caused serious side effects. The second biopsy revealed rimmed vacuoles, and the diagnosis of s-IBM was confirmed. The role of clinical, pathological, and electrophysiological features for early diagnosis of s-IBM and differentiation from PM is discussed.
2026-03-24 | Anti-signal recognition particle antibody-positive immune-mediated necrotising myopathy with inclusion body myositis-like features in a patient with human immunodeficiency virus and syphilis infection.
Inclusion body myositis (IBM) and immune-mediated necrotising myopathy (IMNM) are inflammatory myopathies characterized by specific clinical and pathological features. IBM is associated with human immunodeficiency virus (HIV) infection, whereas IMNM is extremely rare in individuals positive for HIV. To date, no reports have described the coexistence of IMNM and IBM-like pathological features in patients positive for HIV. Herein, we report a rare case of a 40-year-old man with HIV-associated subacute progressive myopathy presenting with simultaneous proximal and distal muscle weakness, dysphagia, and markedly elevated creatine kinase levels. Serological testing revealed strong positivity for anti-signal recognition particle antibodies. Muscle biopsy revealed coexisting pathological features suggesting both IMNM and IBM. The patient showed insufficient response to antiretroviral therapy and glucocorticoids; however, intravenous immunoglobulin therapy resulted in a marked clinical response. This case highlights the possible coexistence of IMNM and IBM-like pathology in the context of HIV infection and provides insights into the pathophysiology of HIV-associated myopathy. Furthermore, this report suggests the potential effectiveness of intravenous immunoglobulin treatment in such cases.
2025-06-26 | Mitochondrial pathology in inflammatory myopathies: a marker of worse clinical outcome.
Mitochondrial dysfunction is well documented in inclusion body myositis (IBM), but its role in non-IBM myositis remains unclear. This study aimed to investigate the prevalence and clinical significance of mitochondrial pathology in non-IBM myositis and to assess its potential role as a marker for disease progression towards IBM, treatment response, and clinical outcomes. Muscle biopsies from 850 patients with inflammatory myopathy (IM) across 6 neuromuscular centers in Italy, France, and Germany were retrospectively analyzed. Inclusion required meeting diagnostic criteria for definite adult IM, mitochondrial pathology (age-exceeding numbers of COX-negative fibers), and exclusion of definite IBM according to Hilton-Jones 2013 criteria. The percentage of COX-negative fibers was quantified, correlated with clinical outcomes, and compared with myositis control cases without relevant signs of mitochondrial alterations. Twenty-five patients with non-IBM myositis and mitochondrial abnormalities were identified. These patients, predominantly women (68%), had a mean onset age of 58.8 years. Polymyositis with mitochondrial pathology (PM-Mito) and nonspecific myositis (NSM) were the most prevalent subtypes (72%). The mean percentage of COX-negative fibers was 3% (0.25-8.5%) in these patients. The presence of mitochondrial pathology was associated with treatment refractoriness and worse clinical outcome evaluated based on residual muscle weakness and the level of independence (p < 0.005). A higher percentage of COX-negative fibers also correlated with poorer clinical outcomes (p = 0.031). Four patients, initially diagnosed with PM-Mito and NSM, progressed to definite IBM. Mitochondrial dysfunction represents a key element informing about disease severity and poor clinical outcomes in non-IBM myositis. It may predict progression to IBM, especially in PM-Mito and NSM, and guide treatment strategies.
2022-07-20 | Botulinum toxin treatment improves dysphagia in patients with oculopharyngeal muscular dystrophy and sporadic inclusion body myositis.
Dysphagia can be troublesome in sporadic inclusion body myositis (sIBM) and oculopharyngeal muscular dystrophy (OPMD), but no established treatment exists. Cricopharyngeal muscle botulinum toxin injection has at case level been reported to be effective. We evaluated safety and efficacy of botulinum toxin injections in the cricopharyngeal muscle in patients with dysphagia due to sIBM or OPMD. Participants were included from our outpatient clinic. Cricopharyngeal constriction was confirmed by laryngoscopy. After EMG confirmation of needle placement in the cricopharyngeal muscle, botulinum toxin A was injected in awake patients. An individualized dose of 5-10 units of botulinum toxin A was applied initially and titrated up a maximum of 3 times. Outcome measures were change in dysphagia questionnaire, timed cold-water swallow test and subjective dysphagia status (worse, unchanged, improved). Due to the need for individualized dosing and a limited number of available patients, an uncontrolled, un-blinded design was used. Thirteen patients, 3 with OPMD, received at least 1 injection. In the dysphagia questionnaire, all but 2 subjects, none with subjective worsening, improved (p < 0.001). Subjectively, seven felt an improvement, 4 no change and 2 a worsening. No overall change was seen the timed cold-water swallow test. No serious adverse events were observed. Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods. EudraCT-number: 2014-002210-23.
2022-07-12 | Inclusion Body Myositis and Neoplasia: A Narrative Review.
Inclusion body myositis (IBM) is an acquired, late-onset inflammatory myopathy, with both inflammatory and degenerative pathogenesis. Although idiopathic inflammatory myopathies may be associated with malignancies, IBM is generally not considered paraneoplastic. Many studies of malignancy in inflammatory myopathies did not include IBM patients. Indeed, IBM is often diagnosed only after around 5 years from onset, while paraneoplastic myositis is generally defined as the co-occurrence of malignancy and myopathy within 1 to 3 years of each other. Nevertheless, a significant association with large granular lymphocyte leukemia has been recently described in IBM, and there are reports of cancer-associated IBM. We review the pathogenic mechanisms supposed to be involved in IBM and outline the common mechanisms in IBM and malignancy, as well as the therapeutic perspectives. The terminally differentiated, CD8+ highly cytotoxic T cells expressing NK features are central in the pathogenesis of IBM and, paradoxically, play a role in some cancers as well. Interferon gamma plays a central role, mostly during the early stages of the disease. The secondary mitochondrial dysfunction, the autophagy and cell cycle dysregulation, and the crosstalk between metabolic and mitogenic pathways could be shared by IBM and cancer. There are intermingled subcellular mechanisms in IBM and neoplasia, and probably their co-existence is underestimated. The link between IBM and cancers deserves further interest, in order to search for efficient therapies in IBM and to improve muscle function, life quality, and survival in both diseases.
small molecules
2026-05-27 | Idiopathic Inflammatory Myopathies-Treatment Perspective of Highly Specialised Rheumatology Centre.
Background/Objectives: Idiopathic inflammatory myopathies (IIMs) are chronic immune-mediated disorders, causing striated muscle weakness and extramuscular symptoms. Real-world, single-centre data are needed to interpret phenotype patterns and evolving therapies. Methods: A single-centre, retrospective cohort study was conducted at the Rheumatology Clinic of the National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland from 1 January 2022 to 31 December 2025. Data included demographics, IIM subtypes, extramuscular involvement, co-existing Sjögren disease (SD), biopsy results, autoantibodies, and treatment. Due to sample size, descriptive analysis was used. Results: The study included 35 patients (31.4% men). Mean age was 50.7 years; mean body mass index (BMI) was 26.0 kg/m2. The cohort consisted of 10 dermatomyositis (DM), one polymyositis (PM), two immune-mediated necrotising myopathy (IMNM), one inclusion body myositis (IBM), 16 anti-synthetase syndrome (ASyS), four juvenile dermatomyositis (JDM), and one clinically amyopathic dermatomyositis (CADM). SD co-occurred in eight cases, including six cases of ASyS. Anti-Jo1 was observed in 13 ASyS cases and one DM. Glucocorticoids (GCSs) were administered in all patients for induction in addition to cyclophosphamide (28.6%), mycophenolate mofetil (MMF) (51.4%), and methotrexate (MTX) (17.1%). Maintenance therapy included MTX (20%), MMF (31.4%), rituximab (34.3%), azathioprine (AZA) (42.9%), and others. Two DM, two JDM, and one ASyS patient received JAK inhibitors, one DM and one JDM anifrolumab, one IBM sirolimus, and four patients with interstitial lung disease (ILD) nintedanib. Conclusions: This Polish single-centre cohort shows effective use of novel therapies for IIM. Sirolimus, JAK inhibitors, and nintedanib were effective. Co-occurrence of SD in ASyS patients requires further research.
2026-03-15 | Modifying muscle metabolic dysregulation in inclusion body myositis with pioglitazone: a single-arm trial.
This single-arm, open-label phase 1 trial evaluated the PPARγ agonist pioglitazone in patients with inclusion body myositis (IBM). After a 16-week observation (lead-in) period, participants received pioglitazone 45 mg daily for 32 weeks. The primary outcome was the change in PPARGC1A expression and related metabolic pathways in muscle after 16 weeks of treatment compared with the lead-in period. Of the 16 enrolled participants, 13 initiated pioglitazone and completed at least one on-treatment assessment; the trial was terminated early due to the COVID-19 pandemic. At baseline, muscle metabolomics revealed broad metabolic abnormalities compared with controls. Pioglitazone reversed elements of this signature, increasing PPARGC1A expression (p = 0.099) and modulating downstream pathways in muscle, including enhanced oxidative phosphorylation. Clinical outcomes were unchanged overall, but a subset with favorable metabolic responses showed slower decline in the IBM-Functional Rating Score (IBM-FRS) and Modified Timed Up and Go (m-TUG). Reported adverse effects included myalgia and heart failure exacerbation. As a phase 1 trial with a limited cohort, these findings provide preliminary evidence that pioglitazone modulates muscle metabolism and warrants further investigation in IBM. This study was supported by the Ira T. Discovery Fund and the Peter and Carmen Lucia Buck Foundation Myositis Discovery Fund. Clinical Trials Registration: NCT03440034.
2026-02-27 | Multilevel impairment of mitochondrial respiration with sex-specific signatures in inclusion body myositis.
Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary tests from RNA level to high-resolution respirometry on permeabilized muscle fibers was performed. The relationship between respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine the clinical significance of the findings. The study included a total of 67 patients with IBM and 45 controls. IBM muscle tissue exhibited reduced maximal respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, males had decreased State 3 intrinsic respiration, whereas females had greater intrinsic respiration in leak states. Complex II control ratio strongly correlated with disease duration and severity only in females. IBM was associated with decreased RNA and protein expression of OXPHOS complexes. Complex I activity was decreased mainly in females. IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that correlated with disease duration in females. In IBM, there was decreased mtDNA content, and impaired mitophagy, both of which strongly correlated with respirometry measures and markers of disease severity, indicating these pathways are likely interconnected and of clinical significance. IBM is characterized by multilevel impairments in mitochondrial coupling efficiency, revealing several potential therapeutic targets to improve mitochondrial fitness, while accounting for sex-specific differences.
2025-11-26 | PO:25:082 | Progressive interstitial lung disease secondary to Sjögren's disease in a patient with inclusion body myositis complicated by dysphagia: a multidisciplinary approach and therapeutic challenges
Background. Inclusion Body Myositis (IBM) is a rare idiopathic inflammatory myopathy, characterized by an insidious onset with progressive muscle weakness and dysphagia. While its association with Sjögren’s syndrome (pSS) has been reported, this overlap is uncommon and often challenging to manage. We present the case of a patient affected by this dual condition, treated at our center. Case report. A 70-year-old man, a former smoker, with a medical history of hypertension, hypothyroidism, transient ischemic attack, and prior intestinal obstruction surgery, presented to rheumatologic evaluation in 2017 with progressive dysphagia and muscle weakness. A diagnosis of IBM was established and confirmed by muscle biopsy. The patient was subsequently treated with intravenous immunoglobulins and pyridostigmine, achieving clinical improvement. In 2023, the patient developed new-onset xerophthalmia, xerostomia, and progressive exertional dyspnea. The comprehensive diagnostic work-up included a chest CT scan showing subpleural reticular thickening, mainly in the posterior-basal segments of the lower lobes, in the lateral segments of the middle lobe, and in the superior segments of the lingula. Pulmonary function testing showed a restrictive ventilatory defect and a moderate drop in DLCO. Serological analysis showed anti-Ro52 antibody positivity, and minor salivary gland biopsy demonstrated a focus score of 1. The overall findings were consistent with pSS. In 2024, due to worsening dyspnea, a new chest CT was performed, showing disease progression with the appearance of pulmonary fibrosis (radiologic UIP pattern). The case was discussed during a multidisciplinary meeting involving radiologists, pulmonologists, and rheumatologists. Due to the clinical and radiological deterioration of pSS-associated interstitial lung disease, treatment with nintedanib 150 mg twice daily, prednisone 50 mg with gradual tapering, and cyclophosphamide according to the NIH protocol was initiated. Maintenance therapy with mycophenolate mofetil 2 g/day was subsequently introduced. At follow-up spirometry, pulmonary function remained stable, although CT imaging showed mild disease progression with increased bronchiectasis. The patient’s clinical and therapeutic management is ongoing under multidisciplinary follow-up. Conclusions. This case highlights two key aspects: the intrinsic complexity in managing inclusion body myositis associated with pSS, and the essential role of a multidisciplinary approach in defining not only the initial treatment but also subsequent therapeutic adjustments based on clinical and instrumental evolution. Furthermore, the combination of an immunosuppressive drug with an antifibrotic agent may represent an effective therapeutic strategy to achieve clinical, radiological, and functional stabilization of interstitial lung disease in patients with pSS.
2025-10-30 | Emerging Treatment Options for Inclusion Body Myositis.
Inclusion body myositis (IBM) is a disabling and progressive muscle disease with no effective disease-modifying therapies. This article summarizes recent advances in IBM therapeutics, analysing the reasons for historic trial failures and highlighting more promising contemporary approaches. Improved understanding of IBM's multifaceted pathogenesis has led to development of targeted approaches-including agents modulating autophagy, myostatin inhibition, and T-cell dysregulation. In addition to pharmacologic interventions, exercise-based strategies, robotics, and surgical procedures are being explored for symptom management. Dysphagia, a major contributor to morbidity, is receiving increased attention through both conservative and interventional approaches.
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2026-07-09 | AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.
Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.
2026-06-02 | Genetic Variation in Follistatin and its Role in Muscle Recovery and Hypertrophy: A Dose-Dependent Mechanistic Review
The Follistatin (FST)--Myostatin axis is a primary regulator of skeletalmuscle plasticity, governing both hypertrophy and regenerative capacity. Whilethe anabolic potential of Follistatin overexpression is well-established, thespecific signaling consequences of graded, physiological perturbations (such asthose arising from natural genetic variation or titrated gene therapies) remainunderexplored. This review synthesizes current literature to distinguish betweenthe effects of binary overexpression versus dose-dependent modulation ofFollistatin. We examine the dual mechanisms of FST action: the canonicalsuppression of Smad2/3 signaling via Myostatin/Activin blockade and thecooperative activation of the Akt/mTOR/S6K pathway through obligate IGF-Ireceptor co-signaling. Emerging evidence from human FST polymorphism studiesdemonstrates that naturally occurring variation in the FST locus tonicallymodulates muscle mass and exercise adaptability across the lifespan. Inparallel, phase 1/2a gene therapy trials show that AAV-mediated FST deliveryproduces measurable functional gains in patients with Becker muscular dystrophyand sporadic inclusion body myositis. The same ligand promiscuity that makesFST potent also renders it hazardous in excess: supraphysiological levelssuppress FSH secretion, impair reproductive function, and, through inadvertentGDF11 inhibition, compromise bone integrity. We conclude that future researchmust map the graded dose--response landscape of FST to define the therapeuticwindow for muscle recovery and hypertrophy while avoiding systemic off-targettoxicity.
2025-12-08 | Antisense oligonucleotides targeting valosin-containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.
Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease presents with variable combinations of inclusion body myopathy, early-onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology. In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5 µM and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39-56]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanised VCP severe A232E pathogenic gene variant (VCP A232E mice) with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95% CI [27-32]) knockdown of VCP protein compared with control ASO. The ASO-mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TAR DNA binding protein 43 (TDP-43) expression, hallmarks of VCP related MSP1. In addition, ASO-treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared with mice treated with control ASO. These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP related MSP1. VCP multisystem proteinopathy 1 is caused by gain-of-function pathogenic variants of the VCP gene. VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). The ASOs reduced VCP, TDP-43, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.
2025-11-19 | Murine toxicology assessment of avgn7.2, a novel gene therapeutic for inclusion body myositis and other muscle wasting diseases.
Sporadic inclusion body myositis (IBM) is a highly debilitating muscle degenerative and rare disease of the middle aged and elderly. Because immunosuppressants fail to prevent muscle wasting in IBM patients and can even exacerbate it, drugs like AVGN7.2 are being developed to halt degeneration and to enhance muscle mass and function. AVGN7.2 is a novel gene therapeutic that attenuates activin receptors through muscle-specific human (h) SMAD7 expression and as part of its preclinical development, we performed a 91-day single-dose toxicology assessment of systemic safety, biodistribution and immunogenicity in accordance with Good Laboratory Practices. Standard physiological, ophthalmoscopic, hematological and serum chemistry examinations were performed and no adverse drug-related effects were detected at any dose (2.3E + 13, 7E + 13 and 2.1E + 14 vg/kg), resulting in a No Observed Adverse Effect Level of 2.1e14 vg/kg. Mice mounted early IgM and late IgG responses to the AAV6 capsid, but no response to the hSMAD7 protein. Vector biodistribution mirrored previously published patterns with liver followed by striated muscle having the highest levels, although overexpression of hSMAD7 and the S6RP biomarker only occurred in muscle. These data suggest that AVGN7.2 was well-tolerated even at doses known to elicit clinical toxicities with muscle-tropic AAV capsids other than AAV6.
2010-07-09 | Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress.
Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. Its muscle-fiber phenotype shares several molecular similarities with Alzheimer-disease (AD) brain, including increased AbetaPP, accumulation of amyloid-beta (Abeta), and increased BACE1 protein. Abeta42 is prominently increased in AD brain and within s-IBM fibers, and its oligomers are putatively toxic to both tissues--accordingly, minimizing Abeta42 production can be a therapeutic objective in both tissues. The pathogenic development of s-IBM is unknown, including the mechanisms of BACE1 protein increase. BACE1 is an enzyme essential for production from AbetaPP of Abeta42 and Abeta40, which are proposed to be detrimental within s-IBM muscle fibers. Novel noncoding BACE1-antisense (BACE1-AS) was recently shown (a) to be increased in AD brain, and (b) to increase BACE1 mRNA and BACE1 protein. We studied BACE1-AS and BACE1 transcripts by real-time PCR (a) in 10 s-IBM and 10 age-matched normal muscle biopsies; and (b) in our established ER-Stress-Human-Muscle-Culture-IBM Model, in which we previously demonstrated increased BACE1 protein. Our study demonstrated for the first time that (a) in s-IBM biopsies BACE1-AS and BACE1 transcripts were significantly increased, suggesting that their increased expression can be responsible for the increase of BACE1 protein; and (b) experimental induction of ER stress significantly increased both BACE1-AS and BACE1 transcripts, suggesting that ER stress can participate in their induction in s-IBM muscle. Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1.
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Drug Discovery Landscape
7 orphan drug designations for Inclusion body myositis.
7 orphan drug designations for Inclusion body myositis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ulviprubart | antibodies | EMA | 2023-07-25 | — | PHARA |
Humanized afucosylated IgG1 monoclonal antibody binding to KLRG1 | antibodies | FDA | 2020-07-07 | — | Abcuro, Inc. |
arimoclomol | small molecules | FDA | 2017-11-02 | — | KemPharm Denmark A/S |
Adeno-associated virus delivered transgene of follistatin | gene therapies | FDA | 2016-09-19 | — | Milo Biotechnology |
Arimoclomol citrate [Miplyffa] | small molecules | EMA | 2016-05-30 | — | Orphazyme A/S |
Bimagrumab | antibodies | EMA | 2012-08-09 | — | Novartis Europharm Limited |
bimagrumab | antibodies | FDA | 2012-06-18 | — | Novartis Pharmaceuticals Corp. |
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