Next generation therapeutics and personalised care for Epilepsy

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1 RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Next generation therapeutics and personalised care for Epilepsy Professor David C. Henshall, Ph.D. Department of Physiology & Medical Physics Royal College of Surgeons in Ireland Biomedical Research Showcase, May 17 th 2016

2 Epilepsy Most common neurological disease affec5ng people of all ages 65 million people worldwide; 40,000 pa'ents in Ireland Costs 15 billion/yr in Europe treatment, A&E, co-morbidities, unemployment... Proper brain func5on requires balanced networks of excitatory and inhibitory neurons Disturbing neuronal networks in the brain Brain becomes hyper-excitable Clinical Neurology, McGraw Hill

3 How do we treat epilepsy currently? An5epilep5c drugs Surgery Other - Diet - Brain s5mula5on Treatment and care of epilepsy pa5ents faces key challenges 30% of pa5ents are drug-resistant Current treatments are not disease-modifying Gene5cs affects drug performance, side-effects Diagnosis, prognosis inaccurate, 5me-consuming...

4 How will epilepsy be treated in the future? 1. New molecular tools and targets An5sense/RNA-targe5ng precision therapies Targe5ng new mechanisms of disease 2. Genomic (precision) medicine CATGCCTA CATGTCGG 3. Future monitoring Direct clinical connec5vity Pa5ent genome sequencing ips lines and gene edi5ng Automated cell phenotyping Personal monitoring devices Biomarker detec5on to inform therapy response Closed-loop feedback-controlled brain s5mula5on

5 1. New molecular tools and targets Epilepsy is a network disease - future drugs will target pathways/gene networks Target regulators of gene networks: microrna microrna are mul4-targe4ng

6 microrna-134 levels are altered in epilepsy Differentiation Apoptosis CHRDL1 DCX Neuronal Migration PUM2 Cofilin PIK2 Actin Polymerisation GluA2 Inhibits/decreases Activates/increases mirna Signalling protein Membrane receptor Cellular process/ characteristic SIRT1 mir134 LIMK Dendritic Spine Density Dendritic Spine Volume CREB BDNF Synaptic Plasticity, synapse formation Long-term potentiation

7 Antagomir-134 reduces seizures in all tested models Next-genera'on an'sense technology uses locked nucleic acid (LNA) for potent and las5ng targe5ng of micrornas kainate pilocarpine pentylenetetrazole Scr Ant134

8 Antagomir-134 prevents epilepsy in all tested models Mouse intraamygdala kainate model of epilepsy months 99.5% fewer seizures Total number of seizures Scr ** Ant134 Rat perforant pathway s5mula5on model of epilepsy Epilepsy PPS rat + Scr PPS rat + Ant-134 4/5 0/5 Norwood, Rosenow; unpublished

9 GapmeR LNA technology will allow precise targeting of any aberrant mrna transcripts Single-stranded antisense oligonucleotides (ASO) for silencing of lncrna and mrna function by RNase H dependent degradation of complementary RNA targets Treat gain-of-function intractable epilepsies

10 microrna-based treatments in clinical trials

11 microrna-based treatment in pre-clinical development for epilepsy Regulus unique antagomir targeting chemistry - 2 methoxyethyl (MOE) and 2, 4 - constrained 2 O-ethyl (cet) into the ribose sugar ring significantly improve both the pharmacokinetic and safety profile An5mir screening

12 Supressing neuroinflammatory networks for disease-modifica5on in epilepsy ATP Sz rates a^er treatment Astrocytosis

13 2. Genomic (precision) medicine Genome interroga5on will transform diagnosis, treatment choice and drug discovery

14 Ireland s unique connected genomics and ehealth network will inform on effective care and drive impactful research 1. Recruitment is na5onal 2. Centres are connected via electronic health records 3. Sequencing is genomic (exome/genome) 4. Result is a stra5fied pa5ent popula5on 5. Provides pipeline for ips, screening etc Sligo University Hospital Cavan/Monaghan Hospital Our Lady s Hospital, Drogheda University Hospital Galway Electronic health records Beaumont Hospital, Dublin St. James Hospital, Dublin University Hospital Limerick University Hospital Waterford Cork University Hospital

15 3. Future monitoring Personal devices for therapy control, seizure predic5on/detec5on Brain stimulation devices Personal monitoring devices Wearable tech Biomarker detec5on to inform therapy response Closed-loop feedback-controlled brain s5mula5on Brain and movement monitoring devices

16 Biomarker discovery provides diagnostic and treatment-monitoring solutions patients healthy control

17 Summary: next genera5on therapeu5cs and personalised care for Epilepsy 1. New molecular tools and targets Treatments that target gene-networks, precision therapies 2. Genomic (precision) medicine Gene5c diagnosis, improved therapy selec5on Na5onal electronic pa5ent records 3. Future monitoring Pa5ent monitoring devices/diagnos5cs CATGCCTA New understanding New treatment New diagnos'cs Health and socioeconomic impacts This is a model for other chronic and rare neurological diseases can be mirrored Gianpiero Cavalleri Jochen Prehn Ray Stallings Beaumont Hospital Norman Delanty Michael Farrell Donncha O Brien Mary Fitzsimons Hany El Naggar