Blockade of nitric oxide-related cell stress as potential treatment for inclusion body myositis

Dr. Jens Schmidt
Clinic for Neurology, University Medical Centre Göttingen, Göttingen, Germany

22nd January 2014

The TACT application submitted for review by Dr Schmidt addresses the potential development of a therapy for inclusion body myositis (IBM). Preclinical data from Dr Schmidt and others has shown a unique interplay between inflammatory and degenerative mechanisms in IBM pathology. Cell culture models showed that exposure of muscle cells to IFN-γ and IL-1β induced intracellular up-regulation of amyloid precursor protein and accumulation of β-amyloid). A subsequent study showed that NO is an important mediator of these interactions and that blockade of inducible NO synthase (iNOS) in vitro reduced NO-mediated toxicity and subsequent accumulation of amyloid in muscle cells . Dr Schmidt asked the TACT committee for specific guidance in translating this hypothesis into a clinical trial in IBM patients. Specifically, guidance was requested with regards to the identification of a lead compound, with plans to take this compound into eventual human trials. Different compounds were discussed, among them the iNOS blocker 1400W. Overall, the TACT committee recognized the unmet need for therapies for IBM, but showed little enthusiasm for pursuing drug development of 1400W, which seems unlikely to have a clear route forward to human trials. However, there was significant enthusiasm for further preclinical testing with other potential compounds, e.g. those that are currently in clinical development.

12 Apr 2017