SMA Europe Call for Projects 2013
Als Ergebnis des Calls 2013 fördert SMA Europe in den Jahren 2014 und 2015 folgende neue Projekte:
George Mentis, Columbia University, New York, USA
„Cellular basis of motor circuit Dysfunction induced by SMN deficiency“
SMA is a childhood neurodegenerative disease for which no effective treatment is currently available. This project aims to determine the cellular basis of motor circuit dysfunction that is caused by SMN deficiency and underlies the disease phenotype in both animal models and human SMA patients.
Eduardo Tizzano, Hospital de la Santa Creu i Sant Pau; Barcelona, Spanien
„Modulating SMN2 splicing with dual inhibitors of Sam68 ans hnRNP A1: A novel therapeutic approach for Spinal Muscular Atrophy“
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that affects 1 in 10,000 newborns, and which is characterized by the degeneration and loss of motor neurons in affected individuals. There is currently no effective cure available or in sight for SMA patients. We know for sure that the disease is ultimately caused by the absence or deficiency of a gene that is precisely called Survival Motor Neuron, abbreviated SMN1.
Although there is currently no cure for SMA, all affected individuals carry in their neurons a potential tool to mitigate or even cure the disease: a second, albeit imperfect, copy of the gene that is lost or inactive, SMN2. No matter how similar to SMN1, however, this second gene is unable to produce the amounts of functional protein (SMN) that would guarantee normal neuron function. Instead, a shorter, non-useful variant of the protein is produced in most cases. We will try to understand why this second gene copy does not work properly in motor neurons of SMA patients, and to find means to induce this gene to produce active protein. In this manner, we hope to save motor neurons and ultimately improve life quality of these patients. Our approach intends to discover compounds that may modulate the intermolecular interactions that promote the production of non-functional SMN protein in SMA patients. We hope that the results of our studies will represent an important step forward towards the design of safe and effective drugs for SMA treatment.
Amparo Garcia-Lopez, Universität Genf, Genf, Schweiz
„Using RNA secondary structure as a therapeutic target for Spinal Muscular Atrophy”
SMA is a neuromuscular genetic disease caused by mutations in the SMN1 gene. The product of this gene is an essential protein for motor neurons called SMN, the levels of which are low in SMA patients. SMN2, a second gene 99% identical to SMN1, can also produce SMN protein, although at insufficient levels. Manipulating SMN2 to increase the amount of SMN protein that this gene generates has proven to compensate for mutations in SMN1, as it successfully reverses SMA-like features in animal models. Thus, the study of factors that regulate SMN2 is of therapeutic interest. Among these factors, an RNA structure called TSL2 plays a critical role. In cell culture experiments, destabilizing the structure of TSL2 using genetic tools can make SMN2 behave as SMN1. This indicates that finding small molecules that can destabilize TSL2 in a similar way could be used as therapies to restore SMN protein in SMA patients.
Although the role of TSL2 in SMN2 regulation has been demonstrated, the use of TSL2 as a drug target is unprecedented for SMA. In this project, we combine computational and experimental tools to obtain the ecessary structural information on TSL2 that will allow us to design molecules capable of destabilizing this RNA. The therapeutic potential of these molecules will be validated by measuring SMN levels in cultured cells from SMA patients and in SMA model flies. To carry out this goal, a multidisciplinary network of international collaborations has been established, which together with our previous experience in therapeutic targeting of RNA will allow us to characterize and exploit TSL2 as a target in SMA for the fist time. We believe that this work will improve our understanding on SMN2 regulation and will contribute with new therapeutic molecules for SMA.