Here, we propose a network-biology based approach to detect and test SMN-independent treatment options. The approval of Spinraza has been a milestone for the treatment of SMA the last years. However, still there are a number of non-responders and many patients have been symptomatic for years. This is a significant problem since a delayed intervention with Spinraza reduces its therapeutic benefit. Since SMN has already been enhanced in Spinraza-treated patients other complementary approaches have to be taken into account. Those are termed SMN-independent approaches. Previously, we and others reported a number of changed signaling pathways with differing potentials as SMN-independent treatments targets. However, signaling pathways act in a network and this network character has been neglected in the SMA-Field so far. Thus, we present novel data on a systems-biology approach towards altered signaling in SMA. We used pre-symptomatic and onset Taiwanese SMA-mice to generate a network of pathways allowing an informed decision for highly connected targets. Those are predicted to redress the equilibrium of the whole network. We will employ a C. elegans SMA model to screen through the network by multiple rescue and pheno-copying experiments allowing us to identify the most potent targets. A validation of these targets on the functional level in C. elegans and an identification of the affected cell-type within the spinal cord of Taiwanese SMA-mice, will allow us to design specific AAV-based treatment approaches. A targeted treatment of the affected cell type in the spinal cord will reduce off-target effects in other cells or tissues. This is important to prevent side-effects a pre-requisite for a now milder clinical phenotype. We will test one target identified by this pipeline in a pre-clinical trial combined with Spinraza. However, our network-biology based pipeline already allowed us to identify B-Raf as a possible target for an SMN-independent approach. B-Raf is an important neurotrophic signaling hub, which is pre-symptomatically down-regulated in spinal cord neurons. Thus we will intrathecally co-apply Taiwanese SMA-mice with an AAV2/1-syn-B-Raf3xFlag together the ASO-10-27, the pharmacological active substance in Spinraza.
Programme SMA Europe, No-profit organisation registered under the German law, SMA Europe Call 2019 – Operating Grant Application
Institute IBBR – Institute of Biosciences and Bioresources
Contact Elia Di Schiavi firstname.lastname@example.org