SMA Europe Call for Projects 2014
Als Ergebnis des Calls for Projects 2014 fördert SMA Europe in den Jahren 2015 und 2016 folgende neue Projekte:
Rubén Artero, Universitat de València, València, Spanien
„A Spinal Muscular Atrophy Drosophila model for in vivo drug discovery“
Spinal Muscular Atrophy (SMA) is an untreatable rare genetic disease caused by lack of SMN protein. Two genes encode human SMN protein. In patients, SMN1 is mutated whereas SMN2 does not encode a correct protein because it lacks a portion of the coding region (exon 7). Boosting exon 7 inclusion is a valid therapeutic strategy. To identify new chemical entities to fight SMA we generated a Drosophila model in which inclusion of human exon 7, in Drosophila motor neurons, produces a light-emitting reporter protein and will use this model to screen for drugs and genes able to enhance exon 7. Because Drosophila has blood brain barrier, identified compounds are more likely to become suitable drugs for the treatment of the disease.
We will validate the relevance of the genes and drugs identified in normal and SMA-derived cell lines. Our previous success with a similar myotonic dystrophy model and the participation of a biopharmaceutical partner provides a scenario that maximizes the chances of finding candidate drugs suitable to therapy development.
Francesco Muntoni, University College London, Großbritannien
„Identification of microRNAs as biomarkers and potential therapeutic targets in spinal muscular atrophy“
With promising therapies progressing through clinical development, there is an urgent need for molecular biomarkers. Biomarkers are medical indicators which show how disease is progressing or how well a therapy might be working. These therefore constitute valuable tools for clinical trials especially if they can be studied using minimally invasive procedures, such as taking a blood sample. This study will seek to identify specific biomarkers called microRNAs. These microRNAs are very small pieces of RNA (nucleic acids similar to the ones that genes are made of) used by cells to control which genes are turned on and off. These have been successfully used in an animal model of Duchenne Muscular Dystrophy and in boys affected by the same condition. The aims of this project will be to:
1. Identify and characterise microRNAs which could serve as biomarkers in SMA.
2. To look at the role of microRNAs in the development of SMA and in the expression of the SMN gene.
3. To establish if microRNAs could be a target for therapeutic intervention.
Martine Barcats, Institut de Myologie, Paris, Frankreich
„Study of the role of SMN in the regulation of muscleresident progenitors for the identification of novel therapeutic targets for SMA“
Muscle defects seen in SMA are partly due to the denervation and loss of the motor neurons that allow them to contract and relax. We know that these motor neurons die because they lack sufficient amounts of a protein called SMN. We also know that muscles react to this low level of SMN.
What is not known is whether the muscle contributes directly to its own problems, independently of the motor neurons. A number of studies support the hypothesis of a muscle-specific role of SMN in SMA.
Dr. Martine Barkats and her team will look at answering this question by:
1. Looking at the role of SMN in the muscle’s progenitor cells (Satellite cells and PW1+ interstitial cells), which are stem cells that are triggered into action to repair any damage done to the muscle.
2. If SMN is absent, do these repair cells still work?
The long term aim is to identify new targets specifically affected in SMA satellite cells, and see if gene therapy targeted at these cells would benefit the muscle damage seen in SMA.
Wilfried Rossol, Emory University School of Medicine, Atlanta, USA
„Rescue of SMA phenotypes by restoring mRNP function“
The motor neuron disease SMA is caused by defective RNA-protein complex assembly and RNA processing, but the mechanisms leading to a specific dysfunction of the motor system is unknown. SMN plays a role in the assembly of complexes that are essential for mRNA splicing in all cell types, but it is unclear how splicing defects may cause the nerve defects and motor neuron degeneration observed in SMA.
Previously, we have observed that reduced SMN protein levels leads to specific defects in the axonal localization of certain mRNAs and mRNA-binding proteins in motor neurons. Based on these results we propose an additional role of SMN in the regulation of axonal mRNA transport, potentially through mediating the assembly of mRNA and associated proteins into neuronal mRNA transport granules. Our model may provide an explanation for motor neuron specific defects in SMA. However, the extent of SMA specific mRNA localization defects and their contribution to the disease phenotype are still unknown.It is the objective of this project to test our hypothesis and find out whether specific defects in the assembly and localization of mRNAs in motor neurons contributes to the synaptic defects observed in SMA. To achieve this goal, we propose to restore mRNA delivery in SMA patient stem cell-derived motor neurons and SMA mouse models, and to investigate to what extent this strategy will rescue the SMA phenotype.
Our results will lead to a better understanding of the role of mRNA localization defects in motor neuron degeneration in SMA. Our findings may pave the way to the development of new therapeutic strategies for the cure of this devastating disease.