Professor Jonathan Barratt (firstname.lastname@example.org),
Dr Neha Dhami (UCB); Dr Jing Zhang (UCB)
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.
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.