The ENTRY-DM Doctoral Network, funded under the prestigious Marie Skłodowska-Curie Actions – Doctoral Networks (MSCA-DN) programme, is offering 14 fully funded PhD positions across leading European institutions. Join ENTRY-DM and contribute to the next wave of RNA-based therapeutics for myotonic dystrophy, a field at the cutting edge of precision medicine and molecular therapies. Be part of a transformative research network that will shape the future of rare disease treatment. Myotonic dystrophy (DM) is the most common inherited muscular dystrophy in adults. It is a complex multi-systemic disorder, impacting not only skeletal and cardiac muscle but also the nervous system, among others. Despite recent advances in understanding the genetic and molecular mechanisms of DM, no effective treatment is currently available. The use of antisense oligonucleotides (ASOs) to counteract the disease-causing mutant RNA has faced delivery challenges and insufficient therapeutic efficacy. The development of clinically viable RNA-targeted therapeutics requires overcoming key scientific and technological hurdles, including poor ASO biodistribution, limited penetration of critical tissues, and the lack of reliable biomarkers to monitor disease progression and treatment response.
ENTRY-DM aims to transform the therapeutic landscape for DM by training a new generation of creative PhD researchers in a structured, interdisciplinary research programme. The project will focus on three major research objectives:
- Development of innovative disease models and exploring disease mechanisms.
- Optimising ASO-based therapies.
- Defining clinical biomarkers for clinical trials.
PhD researchers will investigate genotype-phenotype correlations and RNA dynamics, leveraging cutting-edge genomics, bioinformatics, stem cell research, bioengineering of innovative 3D disease models, medicine chemistry, advanced imaging techniques, as well as neuropsychology approaches and clinical applications, in a truly multidisciplinary project.
Projectdiscription The goal of this project is to develop patient-specific neural models studying the neuropathological processes affected by DM1- and DM2-related repeat expansions. DC7 will use established robust protocols for differentiation of patient hiPSCs to neural lineages, including excitatory cortical neurons, inhibitory neurons and astrocytes. As control for further experiments, DC7 will use iPSCs from healthy individuals and also generate isogenic hiPSCs from DM1-patient lines in which the repeat has been removed by a dual CRISPR/Cas9-NHEJ protocol. DC7 will use the established neural models for functional evaluation of the efficacy of ASO and antagomirs.
To this end, DC7 will conduct extensive analyses of the differentiated iNeurons and astrocytes following therapeutic intervention. These will include morphological analysis, cell intrinsic properties, neural network activity and parameters associated and brain cell phenotypes, such as the number of foci, alternative splicing. iNeurons co-cultured with astrocytes on microelectrode arrays (MEA) will be used to non-invasively measure spontaneous neural network activity before and after treatment.
RUMC has benchmarked the robustness and sensitivity of MEA-derived neuronal activity patterns for multiple different neurodevelopmental disorders. DC7 will combine the MEA measurements with RNA sequencing (MEA-seq) to identify deregulated expression and splicing of genes to identify mechanisms that are relevant to DM-neuropathology and rescued by therapeutic strategies.