Novel therapeutic approaches for neuromuscular diseases

Neuromuscular diseases (NMDs) are a vast group of hereditary or acquired disorders which affect components of the peripheral nervous system (PNS) and / or skeletal muscle. In this thesis, we present new therapeutic approaches towards two diseases from this spectrum of mostly rare, but severe, disorders. The first disease, myotonic dystrophy type I (DM1), is a multisystemic genetic disorder that predominantly affects skeletal and cardiac muscle, but also involves other tissues. The second disease, anti-myelin associated glycoprotein (MAG) neuropathy, is an immune-mediated peripheral neuropathy that affects the peripheral nerve.
DM1 is caused by a mutation in a non-coding region of the dystrophia myotonica-protein kinase (DMPK) gene. The mutation leads to a mutated RNA that binds splicing factors such as muscleblind-like 1 (MBNL1). We developed an in vitro screening assay to identify small molecular weight inhibitors of the toxic RNA-MBNL1 interaction. In one screening project, we screened a collection of isolated natural substances and extracts from plants and fungal strains. This screening led to the identification of several alkaloids that improved aspects of the DM1 pathology in a cell model as well as in a mouse model of DM1. In a second screen-ing project, that was based on a previously described DM1 lead compound, the antiprotozoal pentamidine, we screened a library of antiprotozoal small molecules. Here, we identified di-imidazolines as a new group of small molecules that improved DM1 disease aspects in a cell model of the disease. Compounds from both screens have therapeutic potential for DM1 and RNA-mediated diseases in general, and could serve as valuable starting points for medicinal chemistry programs.
Anti-MAG neuropathy is an antibody-mediated autoimmune disorder. Immunoglobulin M (IgM) autoantibodies targeting the human natural killer-1 (HNK-1) glycoepitope on the mye-lin protein MAG are thought to be pathogenic. Based on the structure of the HNK-1 epitope we synthesized small molecular weight HNK-1 mimetics to block the IgM-MAG interaction. These mimetics were tested in an in vitro competitive binding assay. The mimetic with the closest structural similarity to the natural epitope displayed the strongest inhibitory activity on IgM autoantibody binding to MAG. Using this mimetic, we synthesized a polymer that pre-sents the epitope in a multivalent fashion. This polymer blocked with high efficiency the pathogenic IgM autoantibodies from patient sera. It is biodegradable and could be used as a new therapeutic agent to deplete autoantibodies in the circulation of affected patients.