Neuromuscular disorders: from the omics-age towards novel therapies.

Neuromuscular disorders (NMD) are diverse, usually inheriteddisorders that are chronically debilitating with tremendous societalimpact. We will focus on Hereditary Motor Neuropathies (HMN) andInherited/ Idiopathic Muscle Diseases (IMD). The unmet needs are"missing heritability" and lack of patho-mechanistic understandingand effective therapies. First, we will identify novel genetic causes ofHMN/IMD through advanced genetic studies in large patient cohortswithin international consortia. This allows the identification of rarecauses and unconventional mutation mechanisms. Secondly, basedon our recent identification of α-spectrin mutations in HMN we willstudy the associated spectrum of neuro-spectrinopathies. We willapply advanced machine learning techniques to a custom-builtdatabase featuring known and novel mutations. This will drivemutations modelling in patient derived induced pluripotent stem cellsin order to unravel the roles of the neuronal spectrin-cytoskeleton.Thirdly we will design novel therapies for idiopathic muscle disease,the most important being sporadic inclusion body myositis (sIBM).Using high-resolution proteomics techniques, we found that a keyupstream regulator driving the pathology is KDM5A, a histonedemethylase that induces failure of muscle regeneration in sIBMmuscle. We will use preclinical validation in cellular models to studytherapeutic KDM5A inhibition (pat. pend.) and will seek strategicindustry partners to develop this further.

Keywords:NEUROMUSCULAR DISEASES

Disciplines:Clinical genetics and molecular diagnostics, Neuroanatomy, Neurological and neuromuscular diseases, Neurophysiology