The 2010 Pipeline Conference held in San Francisco 2/25-2/26/2010 provides a window into ongoing research and upcoming possible therapies for epilepsy. The conference was sponsored by the Epilepsy Therapy Project under the direction of Joyce Cramer, with unrestricted educational support from Eisai, Sepracor, UCB, Lundbeck, Pfizer, Upsher-Smith, Cyberonics, Medtronic and an anonymous donor.
Below is a summary of some highlights from the first part of the conference, focusing on devices that work by brain stimulation or direct delivery of drugs or genes to the brain, as well as new approaches to testing in animals before giving treatments to humans. Next month, I will review new drugs in development. Webcasts of the conference will be posted on www.epilepsy.com in a few weeks so you can hear all the details.
Vagus Nerve Stimulation: Cyberonics®, the company that manufactures vagus nerve stimulation, is developing on-demand magnet stimulation that will automatically detect a seizure and activate the magnet. It will include a seizure logging feature as a diagnostic tool. The company also is looking at development of novel stimulation parameters. It is hoping to broaden compatibility of the device with MRI, currently limited to a few MRI machines.
Deep Brain Stimulation of Thalamus: I was the principal investigator for a Medtronic®-sponsored trial of deep brain stimulation for epilepsy, called "SANTE," an acronym for “stimulation of the anterior nucleus of thalamus for epilepsy.” Stimulation proved effective in reducing numbers of partial seizures with or without secondary generalization within 3 months, with further reductions in seizures through 3 years of evaluation. The device is under consideration by the FDA.
Responsive Neurostimulation: Neuropace® has developed an implantable device that can detect seizures and deliver a responsive stimulation to counteract the seizure before it fully develops. The device is entirely implanted into an artificial segment of skull. A study showed efficacy and safety of the system, and benefit was maintained long-term. Further details will be available in the near future, and the device will be under consideration by the FDA.
Seizure Advisory System: NeuroVista® has developed implantable hardware and software that can signal a patient about the likelihood of a seizure in the near future, by use of computer algorithms for analyzing ongoing EEG. Successful studies have been completed in dogs with seizures, and the company is about to enter clinical trials. If seizures can be predicted with some reliability, then the impact of the seizures can be minimized, or treatments initiated at the time of a warning.
Laser Surgery: Visualase® is a company specializing in laser ablation systems, previously used for tumor removal. The laser technology may have applicability for removal of a seizure focus in the brain. Clinical trials are expected to begin in 2010.
Seizure Alert Watches: Two companies, Smart Monitor Corporation® and BioLert®, presented designs of wearable watches that can detect the shaking characteristic of tonic-clonic and tonic seizures. Once a seizure is detected, the watches can send signals to pre-designated cell phones, pagers or other alarm devices. This type of notification may facilitate earlier help during a seizure and peace-of-mind during the quiet times. Clinical trials are underway at Stanford and New York University.
Brain Cooling: The University of Kansas and Flint Hills Scientific® presented a prototype of a probe that could be implanted into brain tissue and cool it to 21°C within 60 seconds. Cooling may provide a reversible way to block brain cell activity, and attenuate seizures.
Local Drug Application to Brain: Orally ingested medicine circulates through the entire brain and body; whereas, local application of a drug to the relatively limited network of brain cells giving rise to seizures might spare the rest of the brain and body from side effects. I performed some of the initial investigations of this technology in laboratory models of epilepsy. Investigators at New York University have carried the idea forward by developing a pump and catheter device to infuse seizure medications under the dura, which is the membrane lining the brain. The drug chosen was muscimol, an analog of the brain's main inhibitory neurotransmitter, GABA. The technology has shown promise in rodents and primates and is now moving towards clinical trials in people with epilepsy.
"Fuss-Free" EEG: Recording of brain waves (electroencephalogram, EEG) is harmless, but sometimes irritating and upsetting, especially to children. A company called Advanced Neurometrics® has developed an EEG system that can apply electrodes via a comfortable cap, with application time in less than five minutes and without leaving any residue on the hair. Quality of the EEG so obtained is good. Product launch is expected in 2011.
Magnetonanoparticles for MRI: Magnetic resonance imaging (MRI) is a very useful clinical procedure that measures magnetic signals in the brain produced by resonance of atomic structures and converts the results to visible brain images. A company called Epinano® has taken this a step farther and linked tiny magnetic particles to chemicals that bind to particular parts of the brain. This enables MRI to visualize special functional systems in the brain, including possibly those associated with epileptic seizures.
Screening Models: H. Steven White, Ph.D., Director of the Anticonvulsant Drug Development Program at the University of Utah, and Stephen Collins, M.D., Ph.D., President of Neurotherapeutics Pharma®, point out that 13 new antiepileptic drugs have been developed since 1993 and many more are under development. All of these drugs have been developed by screening them in animal models of seizures. Models are better for identifying acute seizure blocking ability then for identifying long-term benefit in chronic epilepsy. Current models also are of limited value for detecting side effects. There is a substantial need for better models and better ways to screen for possibly useful antiepileptic medications.
Translational Models of Epilepsies: SynapCell® is a preclinical contract research organization that develops chronic animal models of epilepsy for the purpose of testing new antiepileptic drugs. These models have been invented and validated in academic research laboratories, but the company makes them conveniently available for testing of possible new antiepileptic compounds.
Dog Epilepsy Model: Dogs develop epilepsy more often than do people, and dogs also require treatment for their epilepsy. In the process of treating dogs, information can be obtained that is useful for treating people with epilepsy. The company CanCog Technologies® does not produce epilepsy in dogs, but links a network of veterinary neurologists in the Toronto, Canada region to study antiepileptic drug treatment in canines.
Genetic Models of Epilepsy: Epilepsy can be caused or made worse by genetic factors. The Texas Institute of Genomic Medicine has developed a library of cell clones with more than 10,000 unique gene variants. This library can be used by researchers to determine the role of individual genes in epilepsy or in action of antiepileptic drugs. It is relevant because 99% of human genes have a mouse counterpart and the Institute has available about 70% of existing mouse genes for study.
Blood Test for Epileptic Tendencies: There is presently no blood test that assists with a diagnosis of epilepsy. A company based at UCLA called NeuroIndx®, collected blood tests from rats before and after induction of status epilepticus. About 100 genes were associated with a risk for subsequent development of epilepsy. This approach may be developed to screen people who are at potential risk for epilepsy after brain injuries.
Gene therapy: Gene therapy is a method of designing a gene to replace a defective gene or to supplement a useful function by inserting a gene. Designer viruses usually are used to carry the fabricated gene into brain cells. A company called Neurologix® has developed a method of gene therapy that increases neuropeptide Y (NPY) in hippocampus. Hippocampus, a structure deep in the temporal lobe of the brain, is often involved in seizures. NPY can reduce the excitability of hippocampus. Studies underway with patients suggest that this gene technology is feasible and safe.
Convention-Enhanced Toxin Delivery: Certain toxins may selectively destroy brain cells involved in producing epilepsy. A company called MedGenesis Therapeutics® has collaborated with Dr. Michael Rogawski of UC Davis to develop a method to infuse a selective toxin into brain, by gently pressurizing fluid through a catheter. This causes the toxin to travel through the brain by convection, which is considerably faster than by passive diffusion. It is being tested in animal models and may have applicability to humans.
Inhaling Your AED: Alternate routes besides oral and intravenous administration are of potential value for treating epilepsy. Medkura® is developing an inhalation device to deliver anti-seizure medications. Inhalation of anesthetic drugs has rapidly controlled seizures in mice, and may become a possible new route of therapy for people.
Adenosine-Releasing Implants: Adenosine is a natural neuromodulator released by brain cells after a seizure. It has an inhibitory effect on local tissue. Legacy Research® developed microparticles with embedded adenosine and implanted them in the brains of rats. Electrical stimulation was applied to artificially induce seizures. Rats with inactive particles not containing adenosine developed seizures within 10 days, but seizures did not develop in rats with implanted adenosine particles. This raises the possibility of drug-impregnated implanted nanoparticles into brains of people to prevent or treat epilepsy.
Conclusion: Treatment of epilepsy is no longer limited to drugs, surgery or the ketogenic diet, but now also includes devices. The vagus nerve stimulator is an existing effective device for treating seizures in some people. Many other devices are in development to prevent, ameliorate, terminate, screen drugs for treatment of, predict or notify of seizures. You cannot get these potential therapies now (except for vagus nerve stimulation), but some of these devices should become available in the next 2-10 years.
* Conflicts of interest for author: Dr. Fisher is a paid consultant for NeuroVista® and SmartMonitor® and has done sponsored research for Medtronic®.
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