EU FET Open PRIME project brings together partners from across Europe into a strong multi-disciplinary team. Today we meet the team at Royal College of Surgeons, Ireland (RCSI.)
Who are RCSI?
Founded as the national training body for surgery in Ireland, RCSI has been at the forefront of healthcare education since its establishment in 1784. Today, we are an innovative, world-leading international health sciences university and research institution offering education and training at Undergraduate, Postgraduate and Professional level. RCSI has a long-standing tradition of educational excellence and pioneering new approaches in health sciences research.
Pictured Professor Jochen Prehn and Professor David Henshall.
RCSI is purposefully committed to solving the greatest challenges of modern healthcare. Our translational research enhances patient treatment, informs policy and clinical practice, and improves the quality of education of healthcare professionals. As an exclusively health sciences-focused educational and research institution, RCSI is uniquely placed to drive translational research which benefits patients and the community. We work with industry partners, licensees, RCSI spin-out companies and other key stakeholders across all healthcare sectors to bring our innovative medical research from bench to bedside. EU FET Open PRIME project is embedded in the SFI Research Centre, FutureNeuro, which is focused on finding new treatments and cures for neurological disorders.
Pictured are Dr Rachel Stewart, Ms. Elena Perez Morrissey.
What does RCSI do within EU FET Open PRIME?
We previously identified that tRNA fragments accumulate in the blood in people with epilepsy. The PRIME device being developed will sense local increases in tRNA fragments in the brain and respond with the release of the therapeutic agent GDNF which our partners in Italy have shown to be neuroprotective and capable of preventing further seizures. The research at RCSI contributes to three work packages in the project. In work packages 3 and 4 we are exploring how tRNA fragments affect brain and neuron function by studying their physiological effects in primary mouse cortical neurons and human iPSC-derived cortical neurons and investigating the factors that control the release of tRNA fragments using qPCR, RNA sequencing and mass spectrometry analysis. We are also testing the prototype implantable devices in vitro. . In workpackage 5, we perform the in vivo testing of the encapsulated device system in mice, which will be implanted, adjacent to the hippocampus (a structure in the brain responsible for triggering seizures in people with a common form of epilepsy). We will test the device by dialyzing recombinant epilepsy-associated tRNA fragments adjacent to the device and measuring GDNF release. Once this is found to work, the studies will be run with animals with experimentally-induced epilepsy, to find out if the PRIME device can work autonomously, releasing GDNF in response to changes to tRF levels and lowering the frequency of seizures.
What are the challenges of this project?
In recent years, tRNA fragments have gained a lot of attention as potential key regulators in the cell, however, we are only beginning to uncover their biological functions meaning we still have a lot to discover about how they behave. There are multiple challenges in the project. First, we had used blood data on tRFs and found several different tRFs change in epilepsy. We have had to learn quickly what is happening in the brain and to narrow down the list of tRFs to pick the simplest combination or single tRF for our device. Another challenge is that each model and data source produces slightly different results. We find slightly different chemistry, quantities and packaging of tRFs depending on whether we sample the fluid in the brain (cerebrospinal fluid) or the tissue and whether the sample is from human or has been modelled in a mouse or in a petri dish. Decisions have to be based on finding common and shared mechanisms that will translate; ultimately we want a device that works in the human brain. In vivo testing is also a challenge in several respects. The size of the rodent brain places physical limits on the size of any implanted device, requiring miniaturization during the test phase. The molecules we are measuring being produced and released are at extremely low concentrations requiring very sensitive assays. Finally, spontaneous seizures – epilepsy – are difficult to predict, requiring long-term vigilance to monitor and detect an effect of the device.
How does RCSI collaborate with other partners across the PRIME project?
We collaborate extensively with consortium partners within our work packages to ensure we utilize the expertise and knowledge from each centre to generate great research. Our research is carried out in collaboration with the University of Ferrara (UniFE), Omiics, Tampere University (TAU), EPOS-Iasis, SETU and Aarhus University. We regularly share our findings in group review meetings. In the work package (WP) of Preclinical Experimental Testing and Validation Platform (WP5), we work closely with Omics and UniFE to characterize small RNA profiles in epileptic animal models and patients and learn how to implant and record the function of the PRIME device.
Pictured are Dr Omar Mamad, Dr Alex Nascimento Mr Saad Zaheer.
What excites the team most about PRIME?
Here at RCSI we are most excited about the possibilities of a device that autonomously monitors brain function and reacts to impending seizures by releasing a protective molecule. This would transform the lives of people living with treatment-resistant epilepsy. We deeply enjoy collaborating with such a diverse team spread throughout Europe which incorporates both universities and biotech companies such as Omics. The PRIME project involves people with different skillsets in biological techniques, computational modelling and nanotechnologies which, together with neuroscientists and brain disease experts, creates a powerful team of people to achieve the demanding goals of this project. Epilepsy is a complex neurological disorder which commands inter-disciplinary collaboration to generate therapeutic devices. Ultimately, the most exciting part of this project for us is to be able to generate meaningful scientific data to help improve the quality of life for people with epilepsy.
What are the next steps / milestones for RCSI within the PRIME project?
We are moving into the final stages of the project now, which is particularly exciting. We will be testing ways to detect tRNA fragments and GDNF in the brain and running initial tests of the compatibility and functionality of the PRIME device. We’re also working on some large datasets on the chemistry of tRNAs in different tissues and the mechanisms by which they’re released and absorbed by cells.
