The way into the lung - harnessing virus like particles for CRISPR delivery
(ref. BAP-2025-538)
Laatst aangepast: 19/08/25
Marianne Carlon holds a BOFZAP professorship in the BREATHE lab, the laboratory of chronic respiratory diseases and thoracic surgery, in the faculty of Medicine at KU Leuven. The lab is uniquely positioned at the interface of basic-translational and clinical research, bringing together basic scientists and clinicians working on chronic lung diseases. Prof. Carlon’s team has built an international reputation on understanding and treating the basic gene defect that causes cystic fibrosis (CF). Besides animal models, advanced human in vitro models, such as patient-derived organoid models, are used to validate gene therapy efficacy and safety in the most predictive manner possible (Vidovic et al., AJRCCM, 2016; Maule et al. Nat Commun, 2019; Bulcaen et al., Cell Rep Med, 2024). While gene editing technologies allow to modify almost any genetic target, delivering the CRISPR payload to the right target cell in the lung, is much more challenging. To address this bottleneck, we couple the use of relevant lung models with advanced delivery vehicles to reach this goal. Specifically, we combine the expertise of co-supervisor Prof. Laurens Ceulemans, M.D. (Breathe lab, transplant surgeon), expert in Ex Vivo Lung Perfusion (EVLP) and lung transplantation models, and Prof. Jacob Mikkelsen (Aarhus University, Denmark), a leading authority in virus like particle (VLP) engineering for CRISPR delivery (Haldrup, Nucleic Acids Res. 2023). VLPs will be tailored towards lung-directed delivery by adapting the targeting moieties (e.g. nanobodies) embedded within its envelope. Within KU Leuven, besides working in the BREATHE lab, the Center for Molecular Medicine, to which Prof. Carlon is affiliated, provides the perfect working space for applying state-of-the-art CRISPR and VLP technology to this PhD project. The final goal is to silence relevant targets upregulated during ischemia reperfusion injury (IRI), a major risk factor for reduced lung transplantation outcomes.
Project
The DC11 objectives are:
1) To refine lung-targeting properties of virus like particles (VLPs), also more broadly termed cell-derived vesicles (CDV), to specific lung cell types (airway epithelium, endothelium, resident immune cells) by coupling of ligands (e.g. nanobodies) based on membrane proteins identified in scRNAseq datasets.
2) To screen a library of lung-tropic VLPs to map delivery profiles to the different lung cells using advanced in vitro models.
3) Selected delivery vehicles and gene editors will be tested for optimal delivery, editing and safety in a rodent EVLP system to gene edit relevant genes involved in ischemia reperfusion injury (IRI).
The project will involve experiments using in vitro models (cell lines, primary human lung cells, organ-on-chip, precision cut lung slices). Gene editing experiments in rodent EVLP will be done in collaboration with DC1.
A successful project will result in:
1) Single cell profile of selected VLPs for their cell-specific entry and editing in primary human or rodent lung epithelial, endothelial and immune cell sub-populations.
2) VLP CRISPR silencing of IRI- related target genes, validated using in vitro models and rodent EVLP. 3) thorough safety assessment of both the VLP and gene editing strategy.
Enrolment in Doctoral School: KUL Doctoral school of Biomedical Sciences, Faculty of Medicine
Planned secondments:
- Aarhus University, Denmark: intracellular determinants for efficient pulmonary gene editing (months 15-16)
- Astra Zeneca AB, Sweden: Assessment of safety of VLP-loaded gene editors on immune and genotoxicity in relevant vitro platform (months 26-30)
Profiel
Essential requirements of a successful candidate
- You hold a Master’s degree (no PhD) in bioengineering, biomedical sciences, biotechnology, civil engineering, pharmacy or a related field
- You are passionate about life sciences and engineering, and want to achieve a PhD degree on the topic described in the description above
- You have prior experience, or at least a strong theoretical background, on at least some of the aspects listed above,
- You are ambitious, well organized and have excellent communication skills
- You are proficient in English both spoken and written
- You have a solutions-oriented mindset that thrives in a multidisciplinary team
- You have the ability to work independently and have a critical mindset.
- You are an enthusiastic and motivated person, eager to participate in network-wide training events, international travel and public awareness activities.
Skills and expertise that are viewed as an asset:
- Practical expertise in CRISPR-based genome editing, including guide RNA design, off-target assessment
- Experience in gene delivery technologies, such as lentiviral vectors, AAVs, lipid nanoparticles, or extracellular vesicles and application in cell or animal models.
- Bioinformatics skills in analyzing bulk and single-cell RNA-seq data.
Aanbod
The selected candidates will receive an attractive salary in accordance with the MSCA regulations for Doctoral Researchers (https://www.lifelung.eu/). The exact (net) salary will be confirmed upon appointment and is dependent on local tax regulations and on the country correction factor (to allow for the difference in cost of living in different EU Member States). The salary includes a living allowance, a mobility allowance, and a family allowance (if applicable). The guaranteed PhD funding via the MSCA network is for 36 months (i.e., EC funding). We however provide another PhD year through external funding sources, as to allow the PhD candidate to fulfil a 4-year PhD trajectory, which is standard in Belgium.
https://www.linkedin.com/in/marianne-carlon-56b0b85/
Interesse?
For more information please contact Prof. dr. Marianne Carlon, tel.: +32 16 37 40 37, mail:
[email protected].
Solliciteren voor deze vacature kan tot en met 28/09/2025 via onze online sollicitatietoepassing
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