DM1-MIRNA · New therapeutic targets for DM1: miRNAs analysis in DM1 disease models
FP7 — People (Marie Curie Actions)
- Duration
- 2011-07-01 → 2015-06-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-IRG
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Results in brief
New therapeutic targets for DM1: miRNAs analysis in DM1 disease models
The project titled “New therapeutic targets for DM1: miRNAs analysis in DM1 disease models” (276930-DM1-MIRNA) has targeted different experimental approaches involving miRNAs as suggested important factors in the origin and progression of DM1 rare disease, and because of that opening the possibility of using them a novel therapeutic tools. The project is thought from the a initial set of data obtained mainly from Drosophila studies, but continued on more relevant human samples. Experiments though and performed have mainly targeted (1) the search of new biomarkers for myotonic dystrophy type 1 (DM1), (2) the characterization of how DM1 disease aberrantly regulate miRNAs expression, and (3) what mechanisms are possibly linked to the DM1-miRNA aberrant regulation. The scientific basis for our Project development are linked to recent studies that have revealed new altered cellular pathways in DM1, which suggest the existence of additional players in DM1 pathophysiology still undiscovered and potentially involved in different clinical manifestations in patients. One of the most significant results is the presence of alterations in different microRNAs (miRNAs) in samples from DM1 individuals. As most remarkable in house results, Drosophila studies have allowed the identification of specific miRNAs aberrantly expressed under disease conditions, now considered as therapeutic candidate targets for DM1. Importantly, and bearing in mind how the results most useful for DM1 patients, a more extensive work was done on those miRNAs identified as highly conserved from flies to humans, being also expression levels studied on human samples obtained from DM1 and non-DM1 individuals (fibroblast cell lines from skin-muscle biopsies). Noticeably, miRNAs deregulation detected in flies is also conserved in humans. Together, this relevant data plus additional interesting results regarding miRNAs deregulation in flies DM1 background was published in Human Molecular Genetics Journal (Fernandez-Costa et al., 22(4):704–716, 2013). The well-conserved miRNAs deregulation detected pushed us to target very translational points of view for the further steps to be performed during the project, involving a highly demanded approach in DM1 field, focused on the identification of reliable NON-INVASIVE biomarkers useful for diagnosis, progression and/or validation of therapeutic approaches in DM1. As a summary of the main results achieved during the work performed on this project we can state that: (1) some key deregulation of miRNAs in DM1 disease is highly conserved from flies to humans, (2) different miRNAs are deregulated by different mechanisms in DM1. Specifically, we have detected a potential epigenetic regulation for miR-7 in DM1 by detection of positive methylation when disease is present, and unlike for miR-1 that not displayed methylation differences at any of the situations studied. Otherwise, (3) after an exhaustive study of several circulating miRNAs, we have established that not a reliable DM1 miRNA biomarker exist from the miRNome (175 miRNAs) expressed in human serum. However, the high levels of heterogeneity found from the samples and method we used, combined with positive results from recent publications achieved from other research groups also working on this field suggest and some similarities found with our results suggest to still pursuing a answer for the true identification of non-invasive miRNAs biomarkers for DM1. Importantly, all the work done has tied a strong relationship between researchers and institutions working hard in DM1 field (Dr. López Castel at Valentia BioPharma, Dr. López de Munain at Biodonosti Neuroscience Institute and myself: Dr. Rubén Artero at University of Valencia. Still no socio-economic impact from the results achieved since our more translational approach (biomarker search) has given at this time negative results and no further test through clinical trials possible, although closely linked to this field, the host institution (Valentia BioPharma SL), and thus, the work performed by Dr. Arturo López, is working in the license of a drug candidate for the same disease. All the data related to Valentia BioPharma activities are available on the webpage, where all activities (research projects, results, presentations, direct link to DM1 patients, etc.) can be found.
Data: CORDIS, © European Union
Project objective
Expansion of a non-coding CTG tract in the DMPK gene leads to myotonic dystrophy type 1 (DM1), a dominant autosomal condition clinically characterized by myotonia, muscle waste and heart conduction defects among other symptoms. Transcripts containing long CUG stretches are toxic to the cell by their ability to interfere with gene expression regulation at several levels. Chief molecular alterations are sequestration of MBNL1 and upregulation of CUG-BP1, both alternative splicing regulators, leading to the expression of improper mature proteins. Additional molecular alterations have been suggested to contribute to the elaboration of the disease.We propose that changes in the normal levels of specific miRNAs entail a novel mechanism for DM1. This is supported by recent reports that found miR-206 misregulated in DM1 muscle tissue. Our long term objective is to identify additional miRNA expression alterations and to evaluate their potential as therapeutic targets. To this end, we will make use of two animal models, Drosophila and mice, both transcribing long CTG tracts. First, using complementary approaches of next generation sequencing and commercial real time PCR arrays we will obtain the miRNA expression profile in control and toxic RNA conditions. Second, we will characterize the origin of specific miRNA expression alterations, being suggested misregulated biogenesis, stability loss or direct sequestration by CUG RNA, and will validate the clinical relevance of our findings in DM1 muscle samples. Third, miRNAs relevant to DM1 will be functionally analyzed following loss and gain of function approaches in cell culture and in model animals. Finally, we will evaluate the suppression of toxic CUG RNA phenotypes in DM1 model flies in which expression of altered miRNAs has been artificially restored to assess their potential as therapeutic targets. Although focused in the DM1 human disease, our studies may also lead to important findings in the biology of miRNAs.
Original text from CORDIS.
Participants
- VALENTIA BIOPHARMA SL · PATERNACoordinatorCity levelSpain
Links
Data: CORDIS, © European Union