Evaluation of inhibitory oligotherapy for modulation of immune cells response

Qualification: PhD

Department: Cardiovascular Sciences

Application deadline: 1 July 2021

Start date: As soon as possible

Overview

Supervisors:

Professor Jonathan Barratt (jb81@leicester.ac.uk),

Dr Neha Dhami (UCB); Dr Jing Zhang (UCB)

Project description:

Background: Antisense oligonucleotides (ASOs) are a new emerging class of drugs currently being used for treatment of genetics linked diseases. ASOs are short, synthetic, single stranded DNA oligonucleotides that can alter RNA processing and modulate protein expression. They can be designed to hybridise with RNA to achieve sequence-specific transient knock-down of a target gene. ASOs also require chemical modifications such as phosphorothioate (PS), 2'-O-methoxyethyl (2'MOE) and locked nucleic acids (LNA) which confers intracellular stability to the ASOs through nuclear resistance, enhanced plasma protein binding for increased serum half-life and selective tissue distribution. The primary organs for uptake of oligonucleotides are liver, spleen and kidney. The biodistribution of ASOs to other tissues can be improved using various strategies including peptide conjugation and nanotechnologies.

Aberrant expression of proteins contributes to the pathogenesis of many diseases such as neurodegeneration, autoimmune disease and cancer. ASOs provide an opportunity to halt disease progression by inhibiting proteins with high translation or turnover rates which have previously been considered undruggable with conventional therapeutics. 

Project objective: This PhD project will investigate inhibition of highly secreted proteins from selected immune cell subsets using ASOs as a potential therapeutic modality for hard-to-drug targets.  

The student will discover novel ASOs with optimal chemical modifications targeting immune cells and establish in vitro assays for confirmation of knock-down and determination of off-target effects. This will be followed by in vivo assessment of biodistribution, bioavailability and PK/PD of ASOs in relevant established animal models at University of Leicester. Strategies for efficient therapeutic delivery of ASOs to target cells will also be explored. 

Student experience and skills to be gained: The project is an industrial PhD project with a collaboration between UCB Biopharma SRL and the University of Leicester, UK. The student will work both at UCB (Slough, UK) in a supportive, multidisciplinary Research & Development (R&D) group and in Professor Jonathan Barratt’s lab at University of Leicester. The project will include training in ASO design, in vitro cell-based assays, in both cell lines and primary human cells, followed by investigation of ASO mediated knock-down in an in vivo model. The successful applicant will gain a range of cutting-edge skills in nucleotide-based therapies including gene editing/modulation, RNA and protein analysis and -omics technologies. The student will also develop strong communication and collaboration skills by presenting their results in lab and project meetings, and through in-house events at both UCB and Leicester.

Further reading: 

1. Dhuri, K et al. Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J. Clin. Med. 2020, 9, 2004. 

2. Quemener, AM, Bachelot, L, Forestier, A, Donnou‐Fournet, E, Gilot, D, Galibert, M‐D. The powerful world of antisense oligonucleotides: From bench to bedside. WIREs RNA. 2020; 11:e1594.

Funding

Funding

University of Leicester and UCB Studentship to provide.

  • 3 years stipend at UKRI rates
  • 3 years tuition fees at UK rates

Entry requirements

Entry requirements

Qualifications required: 

Applicants should hold or expect to achieve first/upper-second class Honours degree or equivalent, or a master’s degree in biomedical or related life sciences discipline 

Background or interest in gene therapy approaches (siRNA, CRISPR, ASO), drug discovery, genomics, in vivo mouse biology desirable 

University of Leicester English language requirements may apply.

Informal enquiries

Informal enquiries

Project enquiries to Professor Jonathan Barratt jb81@le.ac.uk

Application advice to pgradmissions@le.ac.uk 

How to apply

How to apply

To apply please click on the Apply Button at the bottom of the page and select September 2021 start.

It is anticipated that the PhD will start as soon as possible.

With your application, please include:

• CV

• Personal statement explaining your interest in the project, your experience and why we should consider you

• Degree Certificates and Transcripts of study already completed and if possible transcript to date of study currently being undertaken

• Evidence of English language proficiency if applicable

• In the reference section please enter the email contact details of your two academic referees in the boxes provided or upload letters of reference if already available.

In the funding section please specify that you wish to be considered for Ref CVS Barratt UCB 2021 
In the proposal section please provide the name of the supervisors and project title (a proposal is not required)

Eligibility

Eligibility

The project is available to UK/ EU applicants only.