Brilliant Idea. Research. Clinical Trials 11/12/15. What Causes Epilepsy? Too Many Causes of Epilepsy: Is There a Common Link? Rare: Genetic Disorders

Transcription

1 Neurology Rehabilitation Brilliant Idea WHY CLINCAL TRIALS AND RESEARCH ARE IMPORTANT Research Jeffrey A. Loeb, M.D., Ph.D. Clinical Trials What Causes Epilepsy? Rare: Genetic Disorders Common: Just about any brain disorder TRAUMA STROKE (From: Wyllie, E. The Treatment of Epilepsy) Too Many Causes of Epilepsy: Seizure: Clinical manifestations of excessive, hypersynchronous abnormal activity of neurons in the cerebral cortex. Is There a Common Link? 1

2 Seizure Epilepsy Epilepsy: Chronic or recurrent seizures. Spread Focus Generalized Epilepsy: Starts on both sides of the brain at the same time Focal Epilepsy: Most common, seizures start from one or more focal regions. Treating Seizures vs. Epilepsy Seizure Treatments (Symptoms): Medications, Diet, Electrical Stimulators Ø Do not cure epilepsy, suppress seizures Treating Seizures vs. Epilepsy Epilepsy Treatments (Cures): Surgery Ø No medications to cure epilepsy Ø No medications to PREVENT epilepsy Epileptogenesis New Medications Treating Seizures vs. Epilepsy The Solution and THE NEED: New Treatments: Disease Modifying Cure or permanently reduce seizures Current Medications Reverse Translational Research Learning from our patients 2

3 11/12/15 REVERSE TRANSLATION Human Brain Tissue Clinical Database Blood/CSF Biomarkers FORWARD TRANSLATION Animal Models Neuropsychiatric Disease Behavior Drug Discovery Small molecules Biopharmaceuticals Clinical Trials Identification and Surgical Removal of Epileptic Foci for Refractory Epilepsy Spiking is far more frequent than seizures: Is this Epilepsy? Spiking is far more frequent than seizures: Is this Epilepsy? 3

4 11/12/15 Too Many Causes of Epilepsy Is There a Common Cause? Study Design What is different between regions of the brain that produce seizures compared to nearby regions that do not? 4

5 Genomics: Genome-wide transcriptome analysis RNAseq Microarray: 43,000 spots where each measures mrna levels of a single gene from a sample of tissue Area of Overlap Suggests Common Pathophysiology Seizure Onset Beaumont TL, Yao B, Shah A, Kapatos G, Loeb JA. (2012) Layer-Specific CREB target gene induction in human neocortical epilepsy, J Neurosci, 32(41): Seizure Onset vs. Interictal Spiking Layer 2/3 Epileptic Activity MAPK CREB Immediate Early Genes Synapse Strengthening and Plasticity Beaumont TL, Yao B, Shah A, Kapatos G, Loeb JA. (2012) Layer-Specific CREB target gene induction in human neocortical epilepsy, J Neurosci, 32(41): Beaumont TL, Yao B, Shah A, Kapatos G, Loeb JA. (2012) Layer-Specific CREB target gene induction in human neocortical epilepsy, J Neurosci, 32(41):

6 11/12/15 Seizure Onset vs. Interictal Spiking Seizure Onset vs. Interictal Spiking Lipovich L, Dachet F, Bagla S, Balan K, Cai J, Jia H, Loeb JA, (2012) Activity-dependent human brain coding / non-coding gene regulatory networks, Genetics, 192(3): Lipovich L, Dachet F, Bagla S, Balan K, Cai J, Jia H, Loeb JA, (2012) Activity-dependent human brain coding / non-coding gene regulatory networks, Genetics, 192(3): Non-Lesional Epilepsy TRANSLATION Human Brain Tissue Clinical Database Blood/CSF Biomarkers Drug Blocks the Epileptic Spiking in Rats Animal Models Neuropsychiatric Disease Behavior Drug Discovery Small molecules Biopharmaceuticals Barkmeier DT,, Senador D, Leclercq K, Pai D, Hua J, Boutros NN, Kaminski RM, Loeb JA. (2012) Electrical, Molecular and Behavioral Consequences of the Interictal Epileptic State in the Rat, Neurobiol Disease, 47(1):

7 Drug Blocks the Epileptic Spiking in Rats Drug Blocks the Epileptic Spiking in Rats Clinical Trials Barkmeier DT,, Senador D, Leclercq K, Pai D, Hua J, Boutros NN, Kaminski RM, Loeb JA. (2012) Electrical, Molecular and Behavioral Consequences of the Interictal Epileptic State in the Rat, Neurobiol Disease, 47(1): Barkmeier DT,, Senador D, Leclercq K, Pai D, Hua J, Boutros NN, Kaminski RM, Loeb JA. (2012) Electrical, Molecular and Behavioral Consequences of the Interictal Epileptic State in the Rat, Neurobiol Disease, 47(1): Neurology Rehabilitation Treating vs. curing epilepsy Learning from our patients Need for new drug targets Need for new types of clinical trial models Support Epilepsy Research! Sharlin Ahmed Shruti Bagla, PhD Karina Balan Daniel Barkmeier MD, PhD Thomas Beaumont MD, PhD Fabien Dachet PhD Jessin John MD PhD Eric Kim (MD PhD student) Biswajit Maharathi (MS student) Sanjay Rakhade MD, PhD Laleh Saadat, PhD Danielle Senador PhD Ruggero Serafini MD, PhD Rick Smith (PhD student) Fei Song MD, PhD Kiyotaka Suwa MD, PhD Helen Wu (MD PhD student) Bin Yao MD, MS Wendy Yang Funding: NINDS/NIH NS049776, R01 NS058802, R01 NS045207, P20 NS080181, Ralph Wilson Foundation, Epilepsy Foundation, WSU Research Enhancement Program, Charles Gershenson Fellowship, John Garvin Chair UIC/Wayne State Collaborators Aashit Shah (Neurology) Darren Fuerst Maysaa Basha Sandeep Mittal (Neurosurgery) Harry Chugani (Pediatric Neurology) Eishi Asano Saba Ahmad Sandeep Sood (Peds Neurosurgery) Rodrigo Andrade (Pharmacology) Nash Boutros (Psychiatry) Jeff Stanley Matt Galloway Farhad Ghoddoussi William Kupsky (Neuropathology Tibor Valyi-Nagy Leonard Lipovich (Genetics) Greg Kapatos Jing Hua (Computer Science) Farshad Fatouhi Yong Xu (Engineering) Jessin John James Patton Jing Li (Pharmacology) Greg Thatcher Other University and Industrial Collaborators Rajeev Agarwal Concordia University RajeevYadav Ed Dratz Montana State University Gal Aviram Amy Bernard Allen Brain Institute Joe Craig Ideacore Ravinder Jilkapally Kourosh Jafari-Khouzani Henry Ford Hospital Raul Krauss Vertex Pharma Rafal Kaminski UCB Karine Leclercq Ben Brown UC Berkeley Sue Celniker Tom Gingeras Cold Spring Harbor 7