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Supervisor: Haiyan Zhou, Mina Ryten, Alice Davidson and Jinhong Meng
Project Description:
Background
Nucleic acid therapeutics (NAT) is one of the most promising and fast-growing class of medicine, which offers great potential to treat rare diseases by addressing the genetic causes in a target-specific manner. The exponential increase in NAT clinical trials in the last few years clearly demonstrates the role of these molecules in translational research and unique opportunities for investigator-led preclinical and clinical studies, in which the UK has particular track record strengths. This PhD project will harnessing the international network and broad expertise from the UK Platform for Nucleic Acid Therapy (UPNAT), a national consortium led by UCL investigators in genetics and NAT fields, to promote the development of NATs for rare disease in the UK (https://rd-research.org.uk/node/upnat/).
Aims/Objectives
The objective of this project is to support the development of a strategic framework and guidelines to assess and prioritise pathogenic genetic variants amenable to NATs, by harnessing the broad network and expertise of UPNAT investigators in genetics and NAT drug development. The project will leverage health data in genomics to identify children with rare diseases who may benefit from the advanced RNA-targeted therapy. We also aim to evaluate the framework by performing further studies on testing antisense oligonucleotide (ASO) therapy to target genetic variants in paediatric neurological diseases, selected using the established guideline.
Methods
The student will be working on collecting and analysing genomic and health data under the supervision and guidance of expert scientists and bioinformatics at UCL and across the UPNAT network, such as the Ryten lab at the University of Cambridge and the Davison Lab at UCL Institute of Ophthalmology. In addition to genetic variants, other factors require consideration, including target cell/tissue-type, disease onset, severity and progression, model system availability, targetability with existing chemistries, informative functional analysis and biomarker(s), opportunistic funding scenarios, and available capacity to conduct a future clinical trial in an established UK clinical research facility.
Multiple scoring systems may be adapted as a quantitative measure to prioritise variants, genes, diseases and patients. To validate the framework, the appointed student will retrospectively assess variants that have already been extensively proven to demonstrate amenability to NATs, in addition to prospective candidates identified as part of the UpNAT framework.
Among the most promising variants, the PhD student will select a promising variant, associated with paediatric neurodevelopmental or neurodegenerative disorders, for NAT design and preclinical development at GOSICH within the Zhou Lab. The student will have the chance to expand their knowledge of the design of different antisense oligonucleotide (ASO) strategies and preclinical ASO drug development in different model systems.
Timeline
- Year 1: Working on UPNAT framework to review anonymised clinical and genetic data to evaluate genetic variants and determine variant effect on transcriptomics by RNA-seq profiling; Determining and prioritizing mis-splicing variants that may be rescued by ASO.
- Year 2: Working on ASO design and preclinical evaluation at RNA and protein levels using relevant cellular model system.
- Year 3: Continue the preclinical validation of lead ASOs on functional restoration and pilot safety study in relevant model system.
References
1. Kim J. A framework for individualized splice-switching oligonucleotide therapy. Nature. 2023
2. Mittal S. Evaluating human mutation databases for "treatability" using patient-customized therapy. Med. 2022
3. Zhou H. Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics. Nucleic Acid Ther. 2023
Contact Information:
Haiyan Zhou