Brain and Spine Curing Spinal Cord Injury (Dr. Labhasetwar) Summary: Stroke Therapy (Dr. Labhasetwar)

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1 Brain and Spine Curing Spinal Cord Injury (Dr. Labhasetwar) Spinal cord injury (SCI) has devastating consequences on those affected, for the rest of their lives. According to the Christopher & Dana Reeve Foundation, more than one million people in the U.S. are living with paralysis due to SCI. Patients with SCI also suffer from other serious complications, such as bladder and bowel problems, heart disorders, and low blood pressure. The costs of living with SCI are considerable, and this condition affects the lives of family members as well, many of whom become round-the-clock caregivers. Despite advances in medical and surgical care, current clinical therapies for SCI are limited. The major challenge is how to inhibit the process of degeneration of injured spinal cord and speed the repair process. In our laboratory research, we have shown that the injured spinal cord can indeed be repaired when treated within a certain time window after the injury, with paralyzed muscles and nerves being restored so that movement is possible again. Our treatment involves a single-dose injection of regenerative therapy that targets the injured spinal cord to begin the repair process. If we can successfully move this research into clinical practice, we can make a real, positive impact on the lives of the many who suffer from SCI. Summary: Dr. Labhasetwar s team has developed a novel therapy, delivered by nanoparticles to injured areas of the spinal cord, to potentially prevent its further degeneration, facilitate repair, and minimize the effects of injury. Stroke Therapy (Dr. Labhasetwar) Stroke is a sudden loss of brain function, most often resulting from interference with the blood supply to the brain. Up to 85% of all strokes are caused by blood clots that block blood supply to the brain. Stroke is a leading cause of death, longterm disability, and costs in both job loss and increased need for health care,

2 highlighting the urgent need for more effective treatments. Giving stroke patients an intravenous dose of tissue plasminogen activator (t-pa) is the only FDAapproved therapy to dissolve blood clots and re-establish blood flow to the brain. However, the period when t-pa treatment can be given is very short, just within 3 hours after a stroke; beyond that window, t-pa puts patients at increased risk of excessive bleeding and brain swelling, so in reality, few patients (1%-5%) have actually benefited from t-pa. A further problem is that injured brain cells deteriorate as time passes, increasing the risks of delayed treatment. If we could extend the crucial time period when we can give therapy to a stroke victim, we could significantly increase the numbers of patients in whom we could prevent further brain damage and facilitate recovery. The Labhasetwar Lab s studies in a model of stroke show that a new nanoparticle treatment is more effective than t-pa alone in restoring blood flow and protecting the brain from further damage over time. This new method may not only benefit more stroke patients but also could significantly improve recovery after a stroke caused by blood clots. Summary: Studies in a model of stroke show that nanoparticle treatment is more effective than blood thinners alone in restoring blood flow and protecting the brain from further damage over time. Reversing Traumatic Brain Injury (Dr. Labhasetwar) Traumatic brain injuries (TBIs) are caused from improvised explosive devices in military combat zones or from explosion-related mishaps involving blast waves, and many TBI patients affected are still young. If we could hasten research in this area, we could restore years of health and productive work to these patients. Blast injuries, with high pressure buildup, cause concussion-like harm throughout the brain and disrupt its protective membrane called the blood-brain barrier (BBB). The initial blast then also sets off a range of other responses in the brain: blood vessels leak, brain and nerve cells die. But in specific research models,

3 nanoparticles loaded with a combination of protective agents have shown promise in crossing the BBB, limiting brain damage, and allowing injured brain and nerve cells and tissues to recover. This line of research holds promise for helping patients to inhibit progressive degeneration of brain and regain some of their former abilities. Summary: Research with nerve-protecting agents loaded in nanoparticles is showing promise for protecting or actually mending areas of the brain after traumatic brain injuries. The Blood-Brain Barrier in Drug-Resistant Epilepsy (Dr. Ghosh) Patients with brain and nervous system disorders, like epilepsy, face two major obstacles to therapy: getting medications across the membrane called the bloodbrain barrier (BBB) and drug resistance, a condition that prevents a patient s medications from working. A task force of The International League Against Epilepsy estimates that 25-30% epileptic patients are resistant to single or combination therapies. So there is a pressing need to develop more effective treatment strategies. The BBB keeps the brain functioning stably, but it can be difficult to get medicines past it into the brain. The research group of Dr. Chaitali Ghosh focuses on drug metabolizing enzymes (cytochrome P450 and UGT) and transporters (MDR1, MRPs) that affect drugs reaching the brain. The interaction of these enzymes with substances may also determine how well anti-epileptic drugs work and how long treated nerve cells survive in the epileptic brain. The Ghosh lab, working with Cleveland Clinic s Epilepsy Center, is pioneering studies about how these enzymes and transporters interact in drug-resistant epileptic patients. The lab is comparing studies with (1) patients brain tissue and blood samples (2) parallel studies using a lab-based BBB model system established with patient-specific brain cells that mimics how the BBB works in the body and (3) results from animal models of how seizures occur. The team is carefully evaluating how regulators (nuclear receptors or transcription factors) work at cellular and molecular levels. With a better understanding of these factors and enzymes in the human epileptic brain, new drugs and approaches to treatment can be precisely designed for individuals who have such brain disorders. With

4 enough support for their continuing advances, the Ghosh lab is poised to help clinicians prevent or treat drug resistance in epileptic patients. Summary: The Ghosh laboratory is studying how anti-seizure drugs work in the body at the point where brain disorders such as drug-resistant epilepsy or epilepsy in patients who also have other conditions (such as stroke, depression, or cancer) are controlled. Models of the Blood-Brain Barrier for Multiple Biomedical Uses (Dr. Ghosh) All the complexities of the living brain cannot be seen, so simplified lab models are needed to simulate how the brain works, in both health and disease. Dr. Chaitali Ghosh is answering this clinical need, leading the way toward precision medicine by creating models of the blood-brain barrier (BBB) that have many potential uses. The BBB is a membrane protecting the brain from foreign substances, but sometimes it can block helpful medications, and it is a great challenge to study. Researchers are aiming for a more complete understanding of the passage across the BBB. The BBB can be damaged by inflammation, infection, traumatic injury, interruption of blood flow (as in stroke), or conditions like epilepsy. Our knowledge of the brain is ever increasing, but we cannot yet tweak BBB functions. And although standard laboratory model systems have provided a wealth of knowledge, it is now evident that newer models are needed, ones that more closely mimic how the BBB acts in the body. Dr. Ghosh s pioneering research is developing user-friendly, humanized BBB models that allow her to explore the BBB under normal and disease states. Her new model systems can reproduce a disease condition by using patient-specific brain cells to create a personalized model; this step is essential for future drug discovery and development. With these models, investigators could test possible medical compounds at the earliest stages to see if they are likely to work or evaluate the effectiveness of currently prescribed medications that cross the BBB. Dr. Ghosh s innovative approach to simulating brain and central nervous system disorders has attracted support from the National Institutes of Health and the American Heart Association. With additional much-needed support, Dr. Ghosh could make even more advances in understanding (1) how drugs penetrate the BBB and how they are taken up at a complex of brain/nerve cells and tiny blood vessels called the

5 neurovascular unit ; (2) how changes in blood flow under stroke-like conditions affect the BBB and drug availability; and (3) how the BBB is involved in cell movement and the targeting of white blood cells to sites of tissue damage in such conditions as multiple sclerosis and epilepsy, to find better treatments. Summary: The Ghosh laboratory is using dynamic, patient-specific BBB models to understand brain activities and the potentially disruptive changes to the BBB caused by brain disorders. Her goal is to tailor research models to specific patients conditions and to improve the availability of medications into the brain for disorders like epilepsy, stroke, and multiple sclerosis. Helping Amputees Feel Through Their Artificial Arms (Dr. Marasco) Nearly 800,000 Americans have lost their upper limbs from civilian or military trauma and could benefit substantially from more functional prosthetic limbs. Many advances have been made in movement control and precise grasping abilities of prosthetic limbs, yet a basic problem remains: Patients with prostheses cannot sense touch, movement, or the position of their artificial limbs. Without this sensory feedback, they must instead watch their prosthesis at all times, preventing multi-tasking and effective control. In the Marasco Laboratory, our primary interest is in building better lines of communication between amputees bionic limbs (fitted with electronics) and their brains. We investigate ways to provide patients with new ways of feeling touch and movement from their artificial limbs. To do this, we focus on how the brain is organized and how it changes to compensate for what has been lost. Using many different model systems with a variety of approaches, we combine results from the lab bench with patients experiences and their input. Doing this helps us to use cognition (thought processes) and perception (information from the senses) to provide amputees with the feeling that their prosthetic limbs are an integrated part of their own body. The patients who collaborate with us have had a surgical procedure to redirect nerves that once served their now-missing limb. Strategic, noninvasive stimulation of these surgically re-wired sites induces the sensation of touch and movement from the missing limb. By linking the sensations to the actions of their prosthesis, we restore a perception of body

6 ownership and agency to these patients, which helps them feel more in control of their prosthetics. With sustained funding, we will continue growing our understanding of how movement and touch sensation allow patients to engage with their prostheses in a natural way. These techniques and technologies may be broadly translated to make a meaningful impact in any situation where the connection between sensation and the brain is disrupted, such as stroke, spinal cord injury, or diabetes. Summary: Dr. Marasco s team is finding new ways to communicate with sensory nerve pathways to provide natural movement and touch sensation for patients with bionic limbs.