Pioneering genomics approaches to develop targeted antisense oligonucleotides for treatment of patients with rare neurological disorders

Academic Supervisors: Prof. Jenny Taylor, Prof. Carlo Rinaldi

Project summary

The increasing availability of whole-genome sequencing (WGS) data, from programmes including 100,000 Genomes Project (100kGP) and the NHS Genomic Medicine Service, is enabling genetic diagnoses to be made for many families with rare genetic disorders. Excitingly, this knowledge is now also providing an opportunity to treat these patients by targeting the genetic variants with nucleic acid therapeutics such as antisense oligonucleotides (ASOs).

We are developing bioinformatics approaches to proactively search these WGS datasets for genetic variants that could be amenable to ASO targeting, such as intronic cryptic splice site variants. We have already identified several candidate genetic variants (e.g., in SCN1A, COASY, and ALDH5A1) and are pioneering expanding this approach to multiple severe neurological disorders, in the first instance.

This project will build on these foundations by enabling students to further develop innovative bioinformatics approaches to search the WGS datasets for ASO-amenable genetic variants in Year 1 and in Years 2-4, to experimentally evaluate candidate variants generating data to support clinical development. The project integrates both computational and wet-lab approaches, offering a unique opportunity for a student to not only identify a genetic variant but also develop an ASO and potentially see it used in patient treatment during the course of the DPhil project.

Lay project summary

Patients and families with rare genetic diseases are increasingly being provided with an explanation for their genetic condition. Whilst having a precise genetic diagnosis is very valuable, families are now very motivated to ensure that this information is also used to inform development of personalized treatments. One such therapy type is called antisense oligonucleotide (ASO) therapy and has been successfully used for the treatment of conditions such as spinal muscular atrophy, a debilitating condition affecting the nervous system and skeletal muscle. We propose to develop ASO approaches using the same widely tested chemistry, targeting different disease-causing genes, thereby expanding the range of rare diseases that can be treated. The project supervisors are members of the UK’s Rare Therapies Launch Pad, which was announced by the Chancellor in the Autumn statement 2023 and highlights the government’s commitment to accelerating development of these therapies.

Project Objectives

1. Identify candidate genetic variants from whole genome sequencing which may be amenable to targeting by ASOs;
2. Functionally validate selected candidate variants which have already been identified, using a combination of relevant wet-lab techniques in patient-derived cellular models;
3. Develop ASOs targeted for the candidate variants using established ASO backbone and modification chemistries;
4. Conduct preliminary assessments of ASO safety and efficacy using the cellular models.

Research Methodologies

• Bioinformatics scripts will be developed to mine WGS data in the Genomics England Research Environment (GEL RE); some scripts have already been developed, but further development is required to capture other relevant variant types e.g. missense, haploinsufficient or allele-specific gain-of-function variants.
• A range of wet-lab techniques will be applied to functionally validate the results – including RT-PCR, RNASeq and minigene assays for splice site validation. Functional assays specific for the gene in question would be developed e.g. enzyme assays, biochemical tests, cellular biology investigations.
• ASO development will utilize well-established chemistries. Validation of ASO effect will utilize the cellular models and assays generated for the functional validation.

Potential Project Impact

The project would aim to deliver 1-3 ASOs that have been shown to target the appropriate genetic sequence and correct the functional defect in in vitro studies, without off-target effects. The data generated could be submitted as part of package supporting a regulatory application. The supervisors are members of the Rare Therapies Launch Pad, which is pioneering expedited regulatory approval for nucleic acid therapeutics.  This, combined with the fact that variants would be identified through WGS datasets where patient re-contact is possible, means that the project could lead to treatment of a patient(s) in the timescale of the DPhil project.

Proposed Project Timelines

Year 1. Learn about the GEL RE, use existing bioinformatics scripts to interrogate the genome sequencing data for candidate variants, optimise the scripts pending outputs;

Year 2. Validate effect of 1-3 genetic variants e.g. by splicing assays and effect on function by assays relevant to gene in question, focusing on in vitro models;

Year 3. Develop ASOs and test for toxicity and efficacy in vitro using the cellular models;

Year 4. Select best ASOs using combined functional data and drawing on known successes and failures in ASPO development to select best candidate(s) for clinical development pathway.

Project Risks & Mitigations

ASOs can fail at various stages of the development pathway. A large pool of candidate variants will therefore be selected in order to maximize the chances of some progressing along the entire pathway. The systematic search of 100kGP and NHS Genome Medicine Service (GMS) datasets can provide a large resource of pathogenic variants potentially amenable to ASO interventions. We have already applied criteria for disease selection (neurological) where intra-thecal delivery mechanisms have been shown to be effective. By selecting a few candidates (e.g. three) for functional studies and multiple ASOs per target site we aim to maximize chance of success.

Training Opportunities

• The Oxford Harrington Rare Disease Centre has close links with the Harrington Discovery Institute in Cleveland USA and opportunities for development of therapeutic candidates.
• The team collaborates with the Nucleic Acid Therapy Accelerator (NATA) and the MRC Rare Disease node led by UCL.
• The project will be part of the Rare Therapies Launch Pad which aims to accelerate the generation of ASO therapies – therefore considerable exposure to clinical, political and regulatory decision-making can be experienced. 
• Rinaldi has biotech start-ups that can provide insight into the commercial ASO development.

Opportunities for student participation in Public and Patient Involvement and Engagement (PPIE)

• Selection of any candidate genetic variants involves contact with the referring clinicians and potentially patient engagement.
• Genomics England has a very active participant panel with members who represent families with rare disease. The Panel members regularly attend conferences and are available for active engagement on projects.
• We have collaborations with several patient organisations including Unique and Genetic Alliance.

Studentship code: MRCTGCORE2025001

Funding Notes

Long-term funding obtained

Application Deadline

12 noon, Tuesday 2nd December 2025

Enquiries

mrccoretg@paediatrics.ox.ac.uk

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For more information on DPhil in Paediatrics: DPhil in Paediatrics | University of Oxford

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