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Population-wide predictive pharmacogenomics for targeted RNA-cleaving and genome editing therapeutics (GEdit-SEQ) (Ref: SF20/APP/MOSCHOS3)

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

In the last decade a sleuth of interventions based on gene therapy and oligonucleotide therapeutics have received regulatory approval, paving the way for the era of personalised and N-of-1 medicine. This has included at least two cases of life-saving advanced molecular therapies designed and produced at scale, for the treatment of specific individuals with unique genetic errors. However, the costs associated to accessing these therapies remain prohibitive for many private and public health care systems.

Biotechnology and pharmaceutical companies typically resort to characterising molecular therapy efficacy on the most commonly encountered patient polymorphisms; the impact of rare variants to drug effect remains understudied. We recently published a targeted RNA-SEQ-based method that uses hypervariable RNA replicon systems to characterise the effect of any possible SNP in the target site of oligonucleotide therapeutics, where cleavage of target RNAs is involved. This was shown to be a quantitative tool, replicating known molecular functions, and identifying opportunities for SNP-depended dose modification strategies to enhance or reduce drug response.

Genome and RNA editing technologies are rapidly progressing from laboratory research tools to promising clinical interventions. Like target-cleaving oligonucleotide therapeutics, genome editors like CRISPR-CAS9 require targeted genome cleavage to exert their action. To date, no solution has been put forward to predict the effect of unexpected patient SNPs on genome editing therapeutics.

This project will involve two phases. In the first phase, the successful applicant will deliver population wide potency data for clinically approved oligonucleotide therapeutics, by testing their effect on custom-build RNA replicon systems. This will include adaptation of RACE-SEQ and RACE-SEQ MM into a semiquantitative RACE method for assessing on-target drug efficacy. In the second phase, the student will seek to develop and deliver a similarly predictive pharmacogenomic tool for DNA-cleaving, genome editing interventions (GEdit-SEQ).

The prospective student will have a background in biological or pharmaceutical sciences, preferably with relevant industry experience. You will work with Associate Professor S.A. Moschos, Associate Professor Ed Schwalbe, and Dr. Andrew Nelson, accessing our world-class third generation sequencing facilities, recently upgraded through an 8 million UKRI grant. You will moreover join a highly energetic, fun, and committed multidisciplinary team with strong humanitarian and commercialisation focus, seeking to translate basic science into patient care.

Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.

For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed. Applications that do not include the advert reference (e.g. SF20/…) will not be considered.
Deadline for applications: 1st July for October start, or 1st December for March start
Start Date: October or March

Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.

Please direct enquries to Dr Sterghios Moschos ( or @docmoschos)

Funding Notes

Please note, this is a self-funded project and does not include tuition fees or stipend; the studentship is available to Students Worldwide. Fee bands are available at View Website . A relevant fee band will be discussed at interview based on project running costs.

References

1. Theotokis, P.I., Usher, L., Kortschak, C.K., Schwalbe, E., Moschos SA. Predicting oligonucleotide therapeutic efficacy at the population level. Hell. J. Nucl. Med. 2019 22(S2): 182.

2. Usher, L., Theotokis, PI. & Moschos, S.A. RACE-SEQ & target SNP testing for endonulceotically active oligonucleotide drugs. Methods Mol. Biol. 2019, 2036:283-305.

3. Theotokis, PI. Kortschak, C., Usher, L. & Moschos, S.A. Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs. Mol. Ther. Nucleic Acids, 2017, 9:22-33.

4. Usher, L., Kortschak, C. & Moschos, S.A. Transitioning RACE-seq, a mechanism of action confirmation assay for DNA-directed RNAi gene therapy, from bench to the bedside. Human Gene Therapy, 2016, 27(7): A13-14.

5. Denise, H., Moschos, S.A., Sidders, B., Burden, F., Perkins, H., Carter, N., Stroud, N., Kennedy, M., Fancy, S.-A., Lapthorn, C., Lavender, H., Kinloch, R., Suhy, D. & Corbau, R. Deep sequencing insights in therapeutic shRNA processing & siRNA target cleavage precision. Mol. Ther. Nucleic Acids, 2014, 3:e145.

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