Group leader: Josep Samitier (email@example.com)
Spinal Muscular Atropy (SMA) is one of the most frequent monogenic neurodegenerative diseases with an incidence estimated to be around 1:6,000 to 1:10,000 in newborns. SMA encompasses a wide clinical continuum of disease severity and has been classified into subtypes according to age at onset and the motor milestones achieved. More than half of patients have the severe phenotype of SMA type 1 with onset of symptoms within the first 6 months of age. Without drug treatment and ventilator support, SMA type 1 is the leading genetic cause of death in early infancy with a life expectancy of under 2 years. SMA type 2 is characterized by a milder course with onset of symptoms between the ages of 6 and 18 months. Per definition, these patients do manage free sitting, but not independent walking. The latter is achieved (at least temporarily) in patients with SMA type 3, whose symptoms’ onset is during infancy or adolescence.
The disease’s hallmark is the degeneration of anterior horn cells in the spinal cord, leading to the characteristic symptom of progressive, proximal weakness involving varying degrees of muscle atrophy. Several different compounds have been investigated in randomized controlled trials in the last few decades. Figure 1 (from Journal of Neuromuscular Diseases 7 (2020) 1–13) shows the main components analysed until now.
The use of induced pluripotent stem cells for disease-modelling, drug-screening and regenerative therapies of NMD has widely evolved in the last years. Nevertheless, few studies have cultured hiPSC-derived motoneurons with hiPSC-derived skeletal-muscle cells in-vitro. Compartmentalized microfluidic culture systems (cµFCS) are microfluidic 2D or 3D cell-culture devices with several compartments interconnected, each mimicking different microenvironment of functional units in organ or tissue level: multicellular architecture, tissue-tissue interfaces (flows and barriers), physicochemical microenvironments (chemical gradients, mechanical strain and electrical stimulation) and pathophysiology. The objective of the thesis is to model the BBB and BSCF barriers (relevant for the gene therapy, antisense oligonucletoide and small molecules treatments) combined with the neuromuscular junction in vitro to model the SMA disease and use the model to analyze the behavior and impact of the different treatments reported until now. There are serious logistical and ethical factors that make additional placebo-controlled usual drug trials difficult if not impossible to carry out now that effective treatment options are available. Considering the limited evidence on the long-term efficacy and safety of novel drug treatments for SMA and their high costs, it is necessary to systematically collect real-world data to improve the basis for clinical decision-making and reimbursement for patients with SMA. In this sense, advanced and personalized models could be strongly relevant.
The thesis is in collaboration and coleader between IBEC and Sant Joan de Deu, for the translational focus. Nanobioenginnering lab from IBEC has a strong experience in microfluidic organ on a chip and in the development of muscular and neuromuscular 3D models. Also, other projects in the group focus in the development of Blood-brain barrier. The group of Sant Joan de Deu, is an international reference in the treatment of SMA patients and in the research on muscular atrophy diseases.
Job position description
The main task of the PhD candidate that will carry out this project is the development of an in vitro models of central nervous barriers as blood-spinal cord barriers blood-cerebrospinal fluid, combined with neuro muscular system. For this purpose, microfluidic design will be used to co-culture and produce 3D central nervous barrier, characterizing their characteristics and permeability. The cell culture will be performed in 3D hydrogels included inside the microfluidic devices. Cells derived from hiPSC will be used to mimic the healthy and SMA disease.
The main aims will be: Develop an predict efficiently and in a fast and reproducible way drug penetration and effect in SMA neuromuscular in vitro model. The specific objectives will include: Fabrication of Microfluid platform and microfluid 3D printing improvement. Development of endothelial-CNS barriers and epithelial-CNS barriers. Analysis of the ECM interaction. Fabrication and integration of biosensors. A systematic study of the barrier permeability. Simulate pathological CNS alterations for SMA and the impact of some drug treatments.
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.