Development of a precision medicine-based gene therapy to treat atherosclerotic disease

Precision Medicine Project - Development of a precision medicine-based gene therapy to treat atherosclerotic disease

Supervisor(s): Prof Andrew Baker, Prof Susan Rosser, Prof David Newby, Prof Judith Sluimer (Maastricht University) & Prof Lars Maegdefessel (Karolinska Institutet)
Centre/Institute: Centre for Cardiovascular Science

Background:

Atherosclerosis is a common chronic vascular condition affecting millions of people. The consequences of atherosclerosis, if left untreated, can be fatal through myocardial infarction and stroke. Despite existing approaches to lower lipids and lipid inflammation, there remains substantive need to design new therapies to prevent progression and rupture of atherosclerotic plaques. With advances in identifying and phenotyping patients with (pre)symptomatic atherosclerosis and the ability to identify different sub-phenotypes of plaques and associated risk, there are clear opportunities to begin to stratify treatment options for sub-phenotypes of atherosclerosis. In particular, the combination of different modalities, including imaging (CT/MRI), morphometric analysis of excised plaques and single cell/spatial technologies now allow deeper phenotyping and, therefore, generation of more informed diagnoses, prognosis and potential for tailored treatments (https://pubmed.ncbi.nlm.nih.gov/35211529/). Herein, this project focuses on the latter, i.e. creation of novel therapeutics bespoke for sub-phenotypes. This will notbe small molecule based, but advanced therapy approaches as we believe that the selectivity in treatment needed for this complex disease can only be provided by modalities such as gene therapy(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417840/). To create these therapies, we can take advantage of network analysis-based knowledge that cell populations and subsets of cells within the atherosclerotic lesion vary widely in both their frequency, transcriptional profile and function depending on the sub-phenotype. We propose to use this available data embedded in ‘omics resources to design, build, test and iterate novel gene therapy solutions for treatment of atherosclerotic sub-phenotypes. We will create these novel gene therapy vector by using the data in two ways that are essential for effective gene therapy. First, we will identify promoters that are targeted for individual cell types/cell subsets and at the same time (2) we will identify or design miRNA (or miRNA combinations) that target transcriptome of the pathogenic cell/subset in a selective manner (https://academic.oup.com/cardiovascres/article/118/4/1004/6184136; https://www.nature.com/articles/d41573-021-00017-7).  Then by design, we will create novel gene therapy systems that incorporate both.

Aims

  1. In the first 2 months, collate relevant human and murine data sets and acquire missing data to identify pathogenic subsets
  2. Computationally interrogate datasets to create cell and subset-specific transcriptional and chromatin maps, CAGE-seq and so on. 
  3. Create approximately 10 selective promoters for each cell/cell subset. Engineer and print genomic plasmid promoters through the Edinburgh Genome Foundry to create plasmids for testing.
  4. Test in relevant model systems; including primary cell cultures, human plaque cultures, mouse models, as required and relevant.
  5.  In parallel to (3-4), map miRNA target prediction tools into the transcription maps of cells/subsets to identify miRNA(s) that will target pathogenic subsets in a selective manner.
  6. Assess miRNA(s) for their ability to target using the models, as described in 4.
  7. Based on 3-6, engineer final candidate constructs with promoters linked to miRNAs for creation and testing of vectors using appropriate models.

Training outcomes

Dual training is provided in wet and computational approaches, coupling to clinical input.

  • Extensive training in bioinformatics and computation approaches to assessment of single cell, spatial, deepSEQ and CAGE-seq data to create the necessary analysis of existing data within the supervisory team and publicly. There are courses in both Edinburgh and Karolinska that will be used, as well as the in house expertise embedded in the Edinburgh and Karolinska labs.  The PhD will also create new data, thus training in single cell technologies, coupling then the wet pipelines to the informatics approaches. 
  • The PhD will develop skills in miRNA bioinformatics (miRNA target prediction) as well as the design and engineering of new promoters, working with the Edinburgh Genome Foundry. Again, this can be provided in the Baker and Karolinska labs, through our existing staff and infrastructures.
  • Clinical input to guide decision making will be important and provided through Newby and his clinical team. The student will be embedded in the Newby group too, with monthly meetings and giving the student access to clinical fellows, and so on. The Newby and Baker labs have excellent joint meetings that will benefit the student. 
  • All skills are within the supervisory team, and the benefit is in the complementary expertise that each supervisor brings.

This is a clear high risk/high reward project to envision parts 1-7. However, there are clear mitigations at each stage to enable effective, collective decision-making about project evolution with respect to both research goals and training needs. Mitigation steps will include go/no go for the promoters based on selectivity levels in initial cell screens; miRNA predictions are of course predictions and initial “mRNA signature” analysis to define miRNA targets will be an early definitive go/no go. The team as a whole will make such decisions in liaison with the student. We will have 3 month project team meetings to allow this as well as embedding the student in the Baker lab, the Karolinska lab and with joint meetings of the Baker and Newby groups.

Apply Now

Click here to Apply Now

  • The deadline for 25/26 applications is Monday 13th January 2025
  • Applicants must apply to a specific project. Please ensure you include details of the project on the Recruitment Form below, which you must submit to the research proposal section of your EUCLID application. 
  • Please ensure you upload as many of the requested documents as possible, including a CV, at the time of submitting your EUCLID application.  

 

Q&A Sessions

Supervisor(s) of each project will be holding a 30 minute Q&A session in the first two weeks of December. 

If you have any questions regarding this project, you are invited to attend the session on Monday 2nd December at 1pm GMT via Microsoft Teams. Click here to join the session.

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