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By Kristy Tsang, on 30 October 2023
In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at UCL, Dr Stephanie Efthymiou highlights her Regenerative Medicine Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to treat the NARS1 disease.
The title of my project is “Development of an iPSc-based organoid model for characterising the NARS1 disease at a cellular level”. It involves the development and characterisation of a comprehensive patient-derived cortical organoid model using human fibroblasts from a NARS1 patient.
Mutations in NARS1 result in neurological disorders, ranging from mild late-onset peripheral neuropathy to severe multi-systemic neurodevelopmental disorders. A third of patients continue to have seizures despite optimal medication. These patients suffer side effects of antiepileptic drugs, have several co-morbidities, experience social exclusion and have a high risk of sudden unexpected death. There are limited pharmacological treatment options for the NARS1 disorder; instead clinical care focuses on managing symptoms with physical therapy. Patients need to take a combination of many medicines to tackle the different symptoms.
Generating and characterising an organoid model from patients will be instrumental in planning an adeno-associated viral (AAV) therapy aiming to rescue the defective NARS1 gene. Overexpression of healthy NARS1, offers an invaluable opportunity of aspiring to normal physical and cognitive development to the people affected by this disease. By using AAV as delivery method we can control the expression of the gene in targeted cells and in the desired dose. AAV therapies have been widely used in the rare disease space and steadily acquiring more and more regulatory approval.
The Regenerative Medicine TIN Pilot Data Fund allows early career researchers like myself to explore new and innovative research ideas as well as develop preliminary data for future fellowship or grant applications. It was therefore a great opportunity for me as I try to take my first step towards independence but also develop an in-vitro model for tacking the NARS1 disease.
The scheme is extremely helpful for early career researchers to learn more about the translational research process. Coming from a genetics PhD and having mostly worked on sequencing patients and identifying novel genes linked with brain function, it helped me become more aware of the translational process, and to think about the potential therapeutic impact of our work. During the preparation for the Dragon’s Den interview, I got to practice and develop my presentation skills in a pitch training event which was very enlightening, and I learned how to focus on relevant information for funders and investors.
Hopefully complete our iPSC reprogramming for at least one patient and one control cell line, that could be used to construct brain assembloids. My aim is to successfully use the in-vitro organoid model to characterise the NARS1 disease on a behavioural and molecular level, and together with an already established in-vivo mouse model we have in the lab, to use the data to plan a future gene-therapy approach that could firstly be used in NARS1 children, and hopefully to other ARS-related disorders.
There’s a lot going on right now – on the science side, we are reprogramming more patient-derived cell lines into iPSCs as part of the TIN project but also with external collaborators abroad. On the translational side, we have partnered with n-Lorem Foundation in the US, to bring individualized antisense oligonucleotide (ASO) medicines to patients with a specific dominantly-inherited NARS1 mutation. Our first patient from Canada has initiated the process and the ASO therapy will soon be developed for her unique mutation. And most importantly on the patients side, we are engaging with parents of NARS1 children through the Rory Belle Foundation, and running a natural history study of the disease on a data collection platform for rare diseases called RARE-X (Global Genes).
Stephanie Efthymiou is a Postdoctoral Research Fellow at the MRC-funded International Centre for Genomic Medicine in Neuromuscular diseases. She completed her PhD studies in the laboratory of Prof. Henry Houlden at UCL Queen Square Institute of Neurology, where she used genomic sequencing approaches to identify novel genetic etiologies in paediatric epilepsies and neuropathies. Her current postdoctoral work in the laboratory of Prof. Mike Hanna involves creating a transcontinental genomics research partnership between the UK and lower and middle-income countries. Her work involves harnessing genomics to improve the lives and health outcomes of children and adults with neuromuscular diseases (NMDs) across the globe.
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