We aim the development of antisense oligonucleotides that block repressive miRNAs (antimiRs and blockmiRs) as well as the use of alternative approaches (drug repurposing) for the identification of drugs capable of treating rare neuromuscular diseases based on the use of innovative therapeutic targets
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Myotonic Dystrophy
Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating disease caused by an expansion of CTG repeats in a non-coding region of the DMPK gene. In mutant DMPK transcripts, CUGs sequester MBNL proteins, which cannot fulfill their normal functions, and originate disease symptoms such as muscle weakness, stiffness, myotonia, and atrophy. However, DM1 is characteristically multisystemic and also affects the heart, the brain, and the smooth musculature.
Among the many therapeutic approaches explored to reverse the pathological manifestations of DM1, our group has pioneered the upregulation of the endogenous MBNL genes as a means to compensate for their abnormal binding to CUG repeats. To this end, we pursue the optimization of antisense oligonucleotides that block repressive miRNAs (antagomiRs). This goal is being targeted mainly through the TATAMI project funded by "Fundació La Caixa". Additional objectives are the identification of novel therapeutic targets and oligonucleotide drugs able to prevent or reverse muscle atrophy and weakness, with particular attention to RNA binding proteins and regulatory miRNAs. These highly translational research make use of patient-derived cells and model mice and require close collaboration with a diverse array of experts in bioinformatics, bioengineering, nucleic acids chemistry, neurology and molecular imaging. This goal is being pursued through the PROMETEO project funded by Generalitat Valenciana. |
Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder caused by the loss of alpha-motor neurons in spinal cord and brain nuclei. The SMA patients have mutated the SMN1 gene, but unaffected the human-specific SMN2 copy, which is translated into partially functional SMN protein.
Current therapeutic strategies are focused on SMN2 splicing modulation to increase Ex7 inclusion in the mature transcript, which generates a more active and stable protein. The FDA-approved drug nusinersen (Spinraza™) is an antisense oligonucleotide that promotes exon 7 inclusion. However, there are still many concerns about the drug administration (intrathecal) and its cost. Also, new evidence shows that a systemic restoration of SMN levels may be needed to complement the nusinersen therapy.
Thus, modulation of the SMN2 splicing by small-molecule drugs is still a much-needed concept to treat SMA. In this regard, we have developed a Drosophila-based reporter system informative of the SMN2 exon 7 inclusion rate and used it for drug repurposing screening in relevant disease cell-types, such as motorneurons. Hit compounds have been validated in patient-derived cells and mouse models moving to translational aims to be developed in CaixaImpulse Validate and AVI projects (see more details here)
You can hear and see about the project progression, funded by the prestigious AFM Téléthon call, in the video below:
Current therapeutic strategies are focused on SMN2 splicing modulation to increase Ex7 inclusion in the mature transcript, which generates a more active and stable protein. The FDA-approved drug nusinersen (Spinraza™) is an antisense oligonucleotide that promotes exon 7 inclusion. However, there are still many concerns about the drug administration (intrathecal) and its cost. Also, new evidence shows that a systemic restoration of SMN levels may be needed to complement the nusinersen therapy.
Thus, modulation of the SMN2 splicing by small-molecule drugs is still a much-needed concept to treat SMA. In this regard, we have developed a Drosophila-based reporter system informative of the SMN2 exon 7 inclusion rate and used it for drug repurposing screening in relevant disease cell-types, such as motorneurons. Hit compounds have been validated in patient-derived cells and mouse models moving to translational aims to be developed in CaixaImpulse Validate and AVI projects (see more details here)
You can hear and see about the project progression, funded by the prestigious AFM Téléthon call, in the video below:
Limb-Girdle Muscular Dystrophy type 1F/D2
Limb-girdle muscular dystrophy 1F/D2 (LGMD1F/D2) is an ultra-rare genetic disease with an autosomal dominant pattern of inheritance. A point mutation in the TNPO3 gene abolishes its stop codon and results in an extended protein variant. The mutant variant shows a compromised importin function and altered cellular localization.
We just generetad the first LGMD1F/D2 animal model using Drosophila, which encompasses two roles: serves as pathogenesis and as a drug screening model. So far we have generated muscle atrophy phenotypes in indirect flight muscles and abdominal muscles that get worse over time, thus confirming its degenerative nature.
We also have the first positive controls for drug screening. In human cells, we are also testing precision medicine approaches to restore a functional stop codon. We intend to provide options for targeted treatment to an uncured till now disease. All this research is being carried out thanks to the funds obtained exclusively by the association of affected by LGMD1F/2D, Conquistando Escalones.
For more information about Conquistando Escalones: http://www.conquistandoescalones.org/web/
We just generetad the first LGMD1F/D2 animal model using Drosophila, which encompasses two roles: serves as pathogenesis and as a drug screening model. So far we have generated muscle atrophy phenotypes in indirect flight muscles and abdominal muscles that get worse over time, thus confirming its degenerative nature.
We also have the first positive controls for drug screening. In human cells, we are also testing precision medicine approaches to restore a functional stop codon. We intend to provide options for targeted treatment to an uncured till now disease. All this research is being carried out thanks to the funds obtained exclusively by the association of affected by LGMD1F/2D, Conquistando Escalones.
For more information about Conquistando Escalones: http://www.conquistandoescalones.org/web/