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CRISPR-activation therapy for macular disease


   Faculty of Biology, Medicine and Health

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  Dr F Manson, Dr T Wang  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Inherited macular dystrophies (MDs) are genetically heterogeneous making a single therapeutic approach difficult. Given the limited therapeutic options there is a critical need for additional therapies, especially ones that are widely applicable. The majority of MD mutations result in proteins that are either less active than normal or are expressed at a lower level than normal. These both outcomes result in decreased functionality, leading to disease. 

This research project will test whether CRISPR-activation (CRISPRa) can correct or ameliorate the abnormal gene expression and cellular function resulting from mutations in genes that cause MDs. CRISPRa gene transactivation works by recruiting transcription factors to the target promoter. The increased gene expression compensates for mutations that either cause proteins to be less active or for less than normal amounts of protein to be made. CRISPRa has already shown great promise as a therapy for a diverse range of human conditions including an inherited retinal dystrophy (1, 2).

 In this project the CRISPRa reagents for each target gene will be optimized in cell lines and transactivation determined by gene and protein expression. Once optimized, the system will be tested in tissue derived from patient induced pluripotent stem cells (iPSCs). In the final stage of the project the functional rescue resulting from CRISPRa will be assessed in retinal tissue. 

The supervisory team have extensive experience in all the techniques to be used in this project. Dr Manson has extensive experience in eye genetics and functional genomics and is using CRISPR in retinal organoids to study eye development and function (3). Professor Wang uses patient-specific iPSCs to study the molecular basis of small vessel diseases (4). Dr Adamson is the manager of the faculty’s Genome Editing Unit and has wide experience in the development and use of CRISPR technologies (5).

Entry Requirements

Candidates will preferably have a Master's degree (at least Merit grade) in a relevant biological science. Lab research experience of molecular biology and cell culture is desirable.

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

How To Apply

To be considered for this Studentship you MUST submit a formal online application form - full details on how to apply can be found on https://www.bmh.manchester.ac.uk/study/research/apply/

Please select PhD Genetics under academic programme when completing your online application. 

Please do not submit an application until you have discussed your suitability to the project with the Primary Supervisor

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/


Funding Notes

Studentship funding is for a duration of 3 years to commence in January 2023 and covers fees, a UKRI equivalent stipend (£16,062 per annum 22/23), consumables and a travel and conference fund.
Funding will cover UK tuition fees and stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a scholarship that will enable a full studentship to be awarded to international applicants. This full studentship will only be awarded to exceptional quality candidates, due to the competitive nature of this funding.

References

1. Colasante G, Qiu Y, Massimino L, Di Berardino C, Cornford JH, Snowball A, et al. In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy. Brain. 2020;143(3):891-905.
2. Böhm S, Splith V, Riedmayr LM, Rötzer RD, Gasparoni G, Nordström KJV, et al. A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation. Science advances. 2020;6(34):eaba5614-eaba.
3. Liu J, Taylor RL, Baines RA, Swanton L, Freeman S, Corneo B, Patel A, Marmorstein A, Knudsen T, Black GC, Manson F. Small Molecules Restore Bestrophin 1 Expression and Function of Both Dominant and Recessive Bestrophinopathies in Patient-Derived Retinal Pigment Epithelium. Invest Ophthalmol Vis Sci. 2020;61(5):28.
4. Kelleher J, Dickinson A, Cain S, Hu Y, Bates N, Harvey A, Ren J, Zhang W, Moreton FC, Muir KW, Ward C, Touyz RM, Sharma P, Xu Q, Kimber SJ, Wang T. Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. Stem Cell Reports. 2019;13(5):817-831.
5. Bennett H, Aguilar-Martinez E, Adamson AD. CRISPR-mediated knock-in in the mouse embryo using long single stranded DNA donors synthesised by biotinylated PCR. Methods. 2021;191:3-14.
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