Postdoctoral studies in Cardiac delivery of therapeutic oligonucleotide conjugates (scholarship)

Do you want to contribute to top quality medical research?

The Department of Laboratory Medicine consists of seven divisions and is active in many areas of Laboratory Medicine. The department is involved in advanced basic scientific, clinical and epidemiological research. The department is one of the largest departments of education at Karolinska Institutet.

Division

Our research efforts in the EL Andaloussi´s lab focus on one of the greatest challenges facing modern therapeutics; the delivery of macromolecules to target cells in vivo. Despite the unprecedented knowledge of diseases and their mechanisms due to advances in biomedical sciences; many promising therapeutic approaches are still clinically unavailable. This is simply because there is no efficient means of delivering these therapeutics to the right organ with the right dose. Our research performance involves developing novel and innovative drug delivery technologies that can carry proteins, RNAs, or gene therapies to the target tissues safely and efficiently. Thus, we engineer exosomes with enhanced delivery and targeting capacities and screen our wide array of exosome designs in disease-relevant cellular and animal models.

Another growing area of research in the Andaloussi lab pertains to the delivery of antisense oligonucleotides (ASOs) that are used to either silence genes or induce splice switching. To enhance delivery of these to specific tissues, different bioconjugation strategies to lipids, peptides or monoclonal antibodies are employed. A major focus is on enhancing delivery of therapeutic ASOs to heart and CNS to treat genetic diseases. In addition to enhancing functional delivery to these tissues, the lab also exploits single cell RNA sequencing to accurately determine tissues distribution within organs on single cell level. This project, which is funded by a recently awarded Novo Nordisk Distinguished Innovator grant, seek to unlock functional cardiac delivery of therapeutic ASOs.

Duties

Within your postdoctoral studies you will study a range of novel ASO-conjugates for their ability to silence genes in cell culture and in mice models, with focus on heart delivery. Firstly, fluorescent ASOs conjugated to a range of ligands will be studied for cellular uptake in different cell lines, including cardiomyocytes, using flow cytometry and confocal microscopy. Subsequently, dose-and time response studies will be performed using qPCR to determine the magnitude of gene silencing with the different conjugates across different cell types. Next, in vivo biodistribution studies will be performed using IVIS imaging, following intravenous or subcutaneous administration.

Plasma will additionally be collected for PK analysis and to study protein adsorption. Lead conjugates will then be tested for functional silencing of target genes in different organs in mice following systemic administration of ASOs. To determine the magnitude of silencing in individual cells, different methods will be employed. In screening experiments, the non-coding RNA Malat-1 and the membrane protein CD47 will be used as targets. These are chosen as they are both ubiquitously expressed body-wide but reside in different cellular compartments. CD47 silencing will be assessed by flow cytometry and immunohistochemistry analysis together with antibodies for staining of specific cell types. Malat-1 silencing will be analyzed using single cell RNA sequencing of cells that have taken up Cy3-labelled ASO conjugates in vivo. Using this methodology, it is possible not only to determine the knockdown levels but also call the identity of the cell types within an organ that have internalized the conjugates. In this way, it is possible to distinguish productive uptake from mere cellular internalization into individual cells in vivo.

Finally, after identifying the best conjugates for cardiac delivery, the ASO sequence will be adapted to target disease relevant genes in models of heart disease. The prospective postdoctoral candidate will work closely with a bioconjugate chemist who will synthesize and provide the different ASO conjugates used within the project.

Entry requirements

Scholarships for postdoctoral qualification can be established for foreign researchers who place their qualifications in Sweden. The purpose of scholarships for postdoctoral qualification is to promote internationalization and contribute to research qualification after a doctorate or equivalent.
A scholarship for carrying out postdoctoral research can be granted for a maximum of two years within a four year period following the receipt of a doctoral degree or equivalent.
To be eligible for a postdoctoral scholarship, the person must have obtained a doctorate or a foreign degree deemed to be equivalent to a doctorate. Applicants who have not completed a doctorate at the end of the application period may also apply, provided that all requirements for a completed degree are met before the (intended) start date of the post doctoral education.

The head of the department determines whether their previous training and scholarly qualifications correspond to a Swedish doctorate or higher.

To be a suitable candidate for the scholarship you should have a solid background in cell biology and extensive experience from cell culture work. Practical lab experience in the following additional areas are required; RNA and protein analysis with qPCR and flow cytometry, experience from laboratory animal work, organ harvesting and single cell isolation from mice as well as immunohistochemistry analysis of tissues. In addition, excellent proficiency in both spoken and written English is important. Strong collaborative skills is a requirement. Experience from RNA sequencing- and bioinformatics analysis is highly meritorious.

As a person We want you to be energetic and passionate and fit in, and actively contribute to our team.

Location: Flemingsberg, Huddinge

Type of scholarship

The amount is tax free and it is set for twelve months at a time, paid out on a six months basis. In exceptional cases, shorter periods may be acceptable.

Application process

An application must contain the following documents in English or Swedish:

• A complete curriculum vitae, including date of the thesis defence, title of the thesis, previous academic positions, academic title, current position, academic distinctions, and committee work
• A complete list of publications
• A summary of current work (no more than one page)

The application is to be submitted on the Varbi recruitment system.

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