Periodic Reporting for period 1 - EpimiRTherapy (Using human tissue to translate microRNA-based therapies for epilepsy)
Reporting period: 2019-12-01 to 2021-11-30
Why is it important for society: Epilepsy is a common neurological disorder which affects around 70 million people worldwide and manifests clinically as the susceptibility to recurrent spontaneous seizures. Roughly 25% of patients do not experience seizure freedom with available anti-epileptic drugs (AEDs). Additionally, adverse effects of AEDs are common due to their non-specific mechanisms of action, and no disease-modifying treatments are clinically available. Consequently, there is an urgent and unmet requirement for disease-modifying therapies in pharmaco-refractory epilepsy, to begin to alleviate the immense socio-economic burden caused by this disease. One of the most promising solutions is antisense knockdown of microRNAs (miRs). MiR levels are dysregulated in brain tissue from humans with epilepsy and in experimental rodent models, and correction of these alterations using antisense oligonucleotides (antagomirs) has disease-modifying anti-seizure effects in in vivo and in vitro (brain slice) models of the disease in rodents. The therapeutic effect of antagomirs has not been verified in human tissue and there remain several barriers to the translation of antagomir therapies for epilepsy to the clinic. Despite its immense promise, ant-134 is not currently being exploited or developed clinically, due to limited evidence of efficacy in humans.
What are the objectives?: 1: Are antimirs taken up in human tissue? (Establish sufficient transfection efficiency). 2: Which human genes and pathways are targeted by miR-134? 3: What are the biophysical effects of miR-134 in human tissue?
miR-134 in rodent epilepsy models: I also performed pre-clinical experiments to interrogate the therapeutic potential of ant-134 in a number of rodent epilepsy models. Work in a P21 mouse model of epilepsy showed for the first time that ant-134 is a viable treatment for epilepsies in juveniles (https://doi.org/10.1038/s41598-020-79350-7). Building on this, work in mouse models of Dravet syndrome and Angelman syndrome, both genetic epilepsy syndromes) generated promising data showing a novel use for ant-134 to treat genetic epilepsies (both publications under review).
Other microRNA targets in epilepsy: As the molecular mechanisms of miR-134 were not conserved in human tissues, I also explored other potential therapeutic microRNA dysregulations in epilepsy models. Notably, my work showed that rational correction of upregulated microRNAs in TLE is therapeutic (http://dx.doi.org/10.1073/pnas.1919313117). More recent work identified miR-335 as a novel microRNA dysregulation in epilepsy. Unlike other upregulated miRs, miR-335 inhibition actually exacerbates seizure phenotypes. Through combined biophysical and molecular analysis, we showed that miR-335 likely acts via VGSC transcripts, and that miR-335 overexpression may be therapeutic.
-Novel insights into the molecular mechanisms of miR-134 in human brain. Impact: Scientists better understand the functions of miR-134 in humans and the implications of this for clinical translation.
-Preclinical evidence that ant-134 is therapeutic in early-onset epilepsies and Angelman syndrome. Impact: new and more precise treatment options for children with seizure disorders and intractable genetic epilepsies.
-Identification of miRs 10, 21, 142 and 335 as therapeutic targets in epilepsy. Impact: In parallel with my work to bridge miR therapies to the epilepsy clinic, I also identified multiple new miR targets which can be progressed in parallel down the same pipeline.
-A novel machine learning approach to seizure detection. Impact: Researchers can quickly and accurately identify and quantify seizures in experimental models. This overcomes limitations of subjective bias and is a tool for higher throughput and more reliable epilepsy research.
-Demonstration of efficacy of BICS01, a new anti-seizure compound. Impact: BICS01 performed better than a frontline AED in seizure models, and therefore may be a highly promising new approach to treating seizures.