Kini: Personalised therapeutic interventions in genetic epilepsies: clinical and molecular approaches

About the Research

Epilepsy is a common neurological disorder affecting 0.5-1% of the population and in ~ 50% of affected individuals a monogenic cause is strongly suspected. Current epilepsy management guidelines are focussed on seizure characteristics but not its causation. There is, however, a growing body of scientific evidence indicating that gene-specific therapy is needed for optimal treatment of genetic epilepsies. While some genetic epilepsies (e.g., channelopathies) are best managed by selecting the most appropriate antiseizure medication based on its mode of action, others may need more bespoke therapy (e.g., metabolic disorders). For some drug resistant genetic epilepsies, molecular therapy may be the only antidote.

Over 1000 genes have so far been identified to cause human epilepsy and 540 of them are routinely tested for in the NHS diagnostic laboratories. The biologic function of the gene is the critical determinant of the best therapy option. Understanding the molecular networks contributing to epilepsy and the impact of gene-directed treatments are likely to inform future global guidelines for epilepsy management and improve clinical outcomes.

The focus of the Kini group (https://www.rdm.ox.ac.uk/people/usha-kini ) is translational research aimed at the diagnosis and treatment of rare neurodevelopmental disorders, where epilepsies are often an important symptom that can affect long-term prognosis.

The group is currently involved in developing new gene-specific guidelines for the management of genetic epilepsies. Our preliminary work has shown that in patients receiving rapid genome sequencing for severe, young onset epilepsy, 59% of patients with a genetic diagnosis had a change in their management. In this project, we will formulate a new consensus guideline focussed on gene-targeted treatment of genetic epilepsies, supported by a systematic review. We will implement this guideline in a clinical setting and evaluate the clinical outcomes.

Objective 1: Conduct a prospective observational study of current practices of epilepsy treatment and measure clinical outcomes. Objective 2: Conduct a systematic review of effective and harmful therapies in genetic epilepsies, by gene type. Through this work, the molecular networks contributing to epilepsy will be analysed, and the optimal treatment by mode of action will be developed. Objective 3: Develop a consensus guideline for management of genetic epilepsies, using the Delphi method. Objective 4: Explore epilepsy-related molecular networks with a focus on genes that result in epilepsy unresponsive to known drugs. Objective 5: Design and perform experiments to develop and validate therapies for gene/s causing drug-resistant epilepsy.

This project will provide the student with opportunities to:

-          Understand the principles of systematic review.

-          Understand the ethical and regulatory aspects of patient-related research.

-          Develop skills in delivering a national prospective study.

-          Understand the principles of developing and evaluating a national guideline.

-          Study the molecular networks that are sensitive to seizure development

-          Develop strategies to deliver genomic therapeutics

Training Opportunities

This is one of the few groups at the University of Oxford focussing on the personalised management of rare genetic epilepsies while using the ‘bedside to bench and back’ approach. While our work on exploring molecular networks to describe novel disease-causing genes continues, we are now using this network approach to not only understand disease mechanism but also to guide personalised therapy. Development of biomarkers to monitor outcome of therapy is also an objective.

This group works well with collaborators nationally and across continents, as is needed to make any research pertaining to rare diseases meaningful.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

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