Advanced personalized extracellular matrix models Collagen VI-Related Muscular Dystrophies to test the safety and efficacy of Nuclei Acid therapeutics

Area of Knowledge: Medicine and Bioengineering

Group Leader:

Josep Samitier, Institute for Bioengineering of Catalonia (IBEC) ·
Nanobioengineering group


Anna Lagunas, Institute for Bioengineering of Catalonia (IBEC) ·
Nanobioengineering group

In collaboration with:

Dr. Cecilia Jimenez · and Dr  Andres Nascimiento ·
Hospital Sant Joan de Deu-Malalties neuromusculars

Research project

There is an urgent need to offer disease modifying treatments for pediatric rare diseases. Neuromuscular diseases have pioneered advances in the therapeutic landscape with some of the most revolutionary and expensive drugs developed to date. These have brought hope to families but also new challenges for public health systems and society. To meet these challenges, we need to work across disciplines and harness the combined potential of technologies such as nanomedicine, bioengineering and gene editing.

Congenital Muscular Dystrophies (CMD) are a heterogeneous group of inherited, rare, and often fatal neuromuscular diseases that cause progressive muscle weakness. Those CMD associated with collagen VI deficiency are the second most common form (with a prevalence between 0.1 and 0.5 per 100,000). Collagen VI-related dystrophies (COL6-RDs) are a group of rare congenital neuromuscular dystrophies that represent a continuum of overlapping clinical phenotypes that go from the milder Bethlem myopathy (BM) to the severe Ullrich congenital muscular dystrophy, for which there is no effective treatment. Patient care relies on managing the serious complications (respiratory insufficiency in severe cases that leads to ventilatory support from age of 10 and scoliosis that require repeated surgery) which limit dramatically the quality of life. To date, there has only been one clinical trial with an anti-apoptotic drug (Omigapil) and a therapeutic study using a low protein diet to activate autophagy. However, these are aimed at non-specific events downstream of collagen-VI and their clinical benefit was unremarkable.

Prof. Jiménez-Mallebrera´s group at Hospital Sant Joan de Déu (SJD) has been working on COL6-RD for over 12 years and is considered internationally as an expert in the field. They have recently demonstrated that a genetic approach based on allele-specific silencing by means of CRISPR/Cas9 and antisense oligonucleotides can effectively correct dominant negative mutations in COL6 genes and restore the biochemical and cellular phenotypes in fibroblasts from patients. In 2020 the Nanobioengineering group at IBEC and the Prof. Jiménez-Mallebrera’s group at SJD pediatric Hospital started a collaboration in which personalized extracellular matrix models of COL6-RDs were developed (Fig 1). Cell-derived matrices (CDMs) from patients were obtained in in vitro cell cultures and analysed by imaging and computational techniques. Results showed that CDMs presented traits that could be ascribed to a particular phenotype and mutation. Therefore, CDMs derived from COL6-RD patients may become relevant preclinical models, which may help identifying novel biomarkers to be employed in the clinics and to investigate novel therapeutic targets and treatments.

In the current thesis proposal, we would like to continue to explore the scope of CDMs preclinical models developed at the Nanobioengineering group at IBEC, which will be applied to test the safety and efficacy of Nuclei Acid therapeutics (NAT), both antisense oligonucleotides and CRISPR/Cas9, that have been designed and validated by Jimenez-Mallebrera´s lab at SJD. To do it, CDMs derived from cells of patients affected by COL6-RDs subjected or not to NAT, and control patients will be investigated combining the previously optical-imaging tools with atomic force microscopy (AFM) analysis to determine the effects on the mechanical properties of the matrices.

The thesis proposed will be in collaboration and in co-leadership between IBEC and SJD, for the translational focus.

Research project:

The overall objective is to study the efficacy and safety of NAT in correcting dominant negative mutations in COL6 genes and restore the biochemical and cellular phenotypes in fibroblasts from patients to facilitate move towards clinical phases of research for a potential curative treatment for COL6-RD. We will make use of the technology previously developed in the Nanobioengineering group at IBEC to produce patient-specific CDMs as physiologically relevant models and we will combine high performance image processing and AFM to develop a reliable diagnostic tool.


The overall objective is to develop a nanomedicine platform to deliver nucleic acid therapies to skeletal muscle as well as to implement physiological in vitro models and advanced tools to monitor the efficacy and safety of these therapies in vitro to move towards clinical phases of research for a potential curative treatment for COL6-RD.

The main task of the PhD candidate that will carry out this project is the development of an in vitro models and increase the efficiency of frug delivery of nuclear acid therapies using nanoparticles.

For the fulfilment of these tasks, the PhD candidate should have a background on bioscience and/or technology such as degree on biology, biotechnology, biomedical engineering or similar. Moreover, knowledge on biology and training on handling laboratory animals shall be considered as assets.

The candidate should have excellent competencies and skills on teamworking, capacity to develop their activity in an interdisciplinary environment, proactivity, commitment, critical and analytical thinking, with high level of English.