sirolimus and Myositis--Inclusion-Body

To provide further evidence for sirolimus, a mammalian target of rapamycin inhibitor, as a treatment strategy for patients with inclusion body myositis (IBM).. We acquired longitudinal clinical data and immunological assessments of CD8. Therapy with sirolimus 2 mg/day by mouth led to rapid and sustained clinical improvement of motor symptoms for an observation period of more than 1 year. Treatment was well tolerated, with no occurrence of adverse effects. We did not observe a meaningful alteration of CD8. The significant and persistent clinical improvement highlights the use of sirolimus as a potential treatment option in patients with IBM. In light of the lack of immunological treatment effects observed for cytotoxic CD8

Topics: CD8-Positive T-Lymphocytes; Humans; Myositis, Inclusion Body; Sirolimus

Topics: Humans; Immunosuppressive Agents; Myositis, Inclusion Body; Sirolimus

Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS.

Topics: Adenosine Triphosphatases; Animals; Autophagy; Cell Cycle Proteins; Disease Models, Animal; Frontotemporal Dementia; Humans; Mice; Muscle Weakness; Mutant Proteins; Myositis, Inclusion Body; Osteitis Deformans; Phagosomes; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Valosin Containing Protein