Mechanism and Potential Treatment of Guillain Barré Syndrome and Related Neuropathy
Abstract
Our proposal is relevant to several areas of encouragement of the Guillain-Barré Syndrome Topic Area and to one area of encouragement in the Emerging Infectious Disease Topic Area. The nervous system is composed of the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS includes the brain and spinal cord and the PNS includes the nerves that project throughout the rest of the body. GBS and a related set of diseases primarily affect the function of nerves. GBS is an autoimmune disease triggered by microbial (bacterial or viral) infection. The GBS autoimmune reaction occurs when the immune system generates antibodies (Abs) against the microbe that unintendedly cross-react with a component of the body. In the case of GBS, Abs mistakenly recognize and damage a protective coating that surrounds the nerves, called myelin. Nerve damage takes place due to the action of a set of immune cells and factors guided to myelin by the Ab. In concert, this constellation of cells and factors attacks myelin in a destructive inflammatory response. Since myelin is required for correct nerve function, GBS results in loss of crucial motor skills. GBS is medically important as there are substantial extended symptoms due to nerve damage. Symptoms can include double vision, difficulty with speech, numbness, pain, difficulty swallowing, sensitivity to light, impaired motor function, and impairment of lung function. Current treatment of GBS is also long-term, intensive, and is typically required for several months. Specific treatment options include admission to intensive care units, heart monitoring, respiratory therapy, physical therapy, blood plasma replacement, treatment with antibody, occupational therapy, and speech therapy. A majority of patients recover after several months, but a significant fraction of patients continues to exhibit permanent nerve damage and have symptoms indefinitely. Animal models are used for research and investigation of human disease to better understand the disease without the risk of harming a human during the process. We have been using a monkey model (also known as a nonhuman primate [NHP] model) of GBS spectrum disease triggered by Zika virus infection. In addition to causing microcephaly and other fetal defects following infection of pregnant women, Zika can cause GBS in adults. We have been studying the response to Zika in the PNS and CNS of the animal model and made the surprising and novel discovery that a specific immune factor appears to be singularly stimulated in neural tissue. Our theory is that this immune factor is likely required for induction of GBS and that blocking the activity of the immune factor is likely to ameliorate GBS induction and symptoms. The activity of this factor requires binding to its receptor on the surface of immune and neural cells. We will test our innovative hypothesis by using a drug that has already been approved by the Food and Drug Administration and that is fortuitously highly specific for this receptor and blocks the binding of the immune factor to the receptor. Since they are genetically and physiologically similar to humans, NHPs are ideal models for modeling, preventing, and treating human disease. NHPs exhibit CNS and PNS development and brain morphology closely resembling humans. In addition, the NHP immune system more reliably parallels the human immune system better than alternative mammal models, such as mice. Drugs developed in NHP models translate to treatments for humans more predictably than those developed in other animal models, and typically drugs developed in other animal models are tested in NHPs prior to human trials. The fact that we will be repurposing a drug already in use, combined with the fact that we will test the drug in our NHP model, should make it possible to rapidly move to clinical use in GBS patients if our hypothesis is correct.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010059
Entities
People
- Antonito T Panganiban
Organizations
- Tulane University of Louisiana
- United States Army