About Research
INTRODUCTION
Astrocytes are the most abundant glial cells in the mammalian central nervous system (CNS). Each astrocyte possesses thousands of individual processes that interact with neurons ensheathing synapses – forming a structure which is now commonly referred to as the “tripartite” synapse (Allen and Barres, Nature, 2009).
The tripartite synapse occurs remarkably frequently in the mammalian cortex, with up to 90% of synapses in mice being tripartite (Genoud et al., Plos Biol, 2006).
This close physical arrangement allows astrocytes to function as critical regulators of synapse development and physiology, through dynamic bidirectional interactions with neurons (Allen and Eroglu, Neuron, 2017).
However, we still do not know enough about astrocyte cell biology and the mechanisms they use to interact with synapses.
Aberrant astrocyte function contributes to major human pathologies characterised by hyperexcitability and aberrant information processing.
Our major lab interests are epilepsy and autism spectrum disorders (ASD) (Jacoby et al., Neurology, 2007; Lord et al., Lancet, 2018), due to their high prevalence and largely unmet clinical need. However, astrocyte pathology has also been observed in neurodegenerative diseases, including Alzheimer’s disease (Forman et al., J Neurosci, 2005), Huntington’s disease (Papalgama et al., Front Mol Neurosci, 2019) and Parkinson’s disease (Kam et al., Neurobio Dis, 2020). About 60% of the European population will suffer at some point in their life from a neurological disease (European Academy of Neurology, www.ean.org, 2022), meaning that as populations increase and age so the socioeconomic burden of these diseases continues to increase.
The basic research performed in the lab of the ERA Chair holder also has translational applications.
In general, a limiting factor in treating CNS disease is the limited access of drugs, particularly large biologics, due to the shielding effect of the blood-brain barrier (BBB). This is unfortunate because of the tremendous therapeutic value of biologics, such as monoclonal antibodies, which have revolutionised treatment in other medical disciplines, especially oncology and rheumatology. However, by leveraging our understanding of basic CNS biology, we have been able to develop a unique strategy for the delivery of such therapeutics into the CNS (Marino and Holt, Front Neurol, 2022) – the so-called ‘biopharmacy’ concept.
This is based on two main principles. First, that BBB crossing AAV (adeno-associated virus) vectors can efficiently carry the instructions for making biologics into the CNS. Second, that astrocytes, as highly secretory cells present throughout the CNS, can effectively be ‘hijacked’, allowing the local and widespread production of therapeutics, at therapeutically meaningful levels. Based on the considerable success we have had with this strategy for the delivery of the anti-inflammatory protein IL2 in traumatic brain injury, stroke and multiple sclerosis (Yshii et al., Nat Immunol, 2022; Patent PCT/GB2020/052148), we have formed a spin-off company, Aila Biotech (www.ailabiotech.com) to capitalise on this work. We are currently expanding the company IP and product range to include a variety of biologics (e.g. nanobodies) active against various targets in CNS injury and disease.
Despite the great potential basic science has to transform modern medicine, our experience with Aila Biotech has proved how difficult it is to take bench science to the bedside. To try and reduce these barriers, the ERA Chair is also responsible for organising and promoting the NCBio Stakeholder Hub. This dynamic organisation serves to facilitate dialogue between basic researchers, clinicians, patient organisations, biotech start-ups, pharmaceutical companies and policy-makers in northern Portugal. Through such a structure, we hope to create an ecosystem that drives socially and commercially transformative science, contributing to the overall.