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Generation of universal donor transplant tissue by genomic engineering of induced pluripotent stem cells


Project Description

Project Description
Blindness can be caused by mutations in genes expressed in the retinal pigment epithelium (RPE), the tissue adjacent to the rod and cone photoreceptor cells that is essential for their normal function. An alternative approach to gene therapy is cell transplantation, an approach that has been pioneered by Japanese researchers who transplanted autologous (i.e. patient’s own) RPE into patients with age related macular degeneration (1). However it would be desirable to be able to use off-the-shelf universal donor cells (2). Despite the eye having a degree of immune privilege there may still be a degree of immunosuppression required when using allogenic cells with compatible leukocyte antigens (HLA) (3).

In this project we will use CRISPR-Cas9 genomic engineering to generate universal donor induced pluripotent stem cells (iPSCs) by knocking out HLA I and II, and then introducing back HLA-E to prevent the activation of natural killer cells (4, 5). These universal donor iPSC will then be differentiated into RPE and functionally characterized.

The student will learn all aspects of cell culture, design and application of CRISPR-Cas9 genome engineering, and cell differentiation and characterisation.

Dr Manson has had a long time interest in retinal degenerations, particularly around bestrophin-1, and has wide experience in model systems and molecular biology. Professor Wang has expertise in the generation of iPSC and their use in disease modeling. The student will also work closely with the Dr Adamson from the University’s Genome Editing Unit who has extensive expertise in the design and application of CRISPR-Cas9.

Entry Requirements:

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are encouraged to apply. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Mandai M et al. Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. N Engl J Med. 2017 Mar 16;376(11):1038-1046.

O'Neill HC et al. Advancing a Stem Cell Therapy for Age-Related Macular Degeneration. Curr Stem Cell Res Ther. 2020;15(2):89-97.

McGill TJ et al. Allogeneic iPSC-Derived RPE Cell Graft Failure Following Transplantation Into the Subretinal Space in Nonhuman Primates. Invest Ophthalmol Vis Sci. 2018 Mar 1;59(3):1374-1383.

Mattapally S et al. Human Leukocyte Antigen Class I and II Knockout Human Induced Pluripotent Stem Cell-Derived Cells: Universal Donor for Cell Therapy. J Am Heart Assoc. 2018 Dec 4;7(23):e010239.

Gornalusse GG et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat Biotechnol. 2017 Aug;35(8):765-772.

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