Their work represents an exciting step forward in our understanding of autoimmune myasthenia gravis and congenital myasthenic syndromes.
“We’re very happy that this year’s expanded awards have brought in outside perspectives to MG research, including researchers who are investigating the structural biology of the acetylcholine receptor and the genetic components and potential treatments of CMS,” Kevin O’Connor, PhD, chief scientific advisor to the MGFA, said. “These projects fill gaps in our current understanding of MG, and are bringing in scientists and scientific fields that had not previously been in the MG research space.”
2023 MGFA Research Grant Recipients
High Impact Pilot Project Award
University of California, San Diego
Amount Awarded: $110,000 over 2 years
Project Funded: Purification of the acetylcholine receptor toward atomic-scale mechanisms underlying MG
Most patients with myasthenia gravis have autoimmune antibodies that attack the connections between their brain and their muscles. The most common target of these antibodies is the protein that sits on the surface of muscles and binds the neurotransmitter acetylcholine. This protein is known as the acetylcholine receptor. When acetylcholine binds the receptor, it opens a hole in the cell membrane that allows ions to permeate the cell. This movement of ions is the event that triggers muscle contraction. Antibodies binding to the receptor interferes with this process, causing progressive muscle weakness. Our ability to treat patients with myasthenia gravis is limited by our knowledge of the receptors and how antibodies attack it. Our long-term goal is to discover, for the first time, the 3-dimensional architecture of the receptor, and how antibodies from patients bind to it. The first major step in this research goal is to purify enough of the muscle acetylcholine receptor, which is the focus of this ambitious pilot proposal. Success in this project will enable success in discovering the structure of the receptor, a process that our laboratory has a strong track record in accomplishing. Having this new information will show, at the level of atomic detail, how antibodies from patients with myasthenia gravis interfere with nerve-muscle signaling. The ultimate goal is to use these discoveries to generate more specific therapies to help patients with myasthenia gravis.
University of California, Davis
Amount Awarded: $110,000 over 2 years
Project Funded: AAV-mediated gene therapy for congenital myasthenia caused by recessive synaptotagmin 2 mutations
The recessive variant of congenital myasthenia linked to the synaptotagmin 2 gene is a newly recognized disorder usually affecting children of consanguineous families. The disease manifests itself at birth with profound weakness, muscle atrophy, and respiratory failure, often requiring mechanical ventilation and gastric tube feeding. Currently available medications are not effective.
This condition results from mutations in the synaptotagmin 2 gene (SYT2), which encodes a protein that is fundamental for the calcium-regulated release of the neurotransmitter acetylcholine at the neuromuscular junction. The genetic transmission of this disorder is recessive, so parents are non-affected carriers, while the disease only expresses in 25% of their offspring. The aim of this project is to develop and obtain FDA approval for a gene therapy based on the delivery of the normal SYT2 gene through an adeno-associated virus vector. After the AAV vector is delivered to the central nervous system, the spinal motor neurons are transduced with the normal SYT2 gene and start translating a normal synaptotagmin 2 protein, which, in turn, is transported through the nerve axoplasmic flow to the neuromuscular junction. This results in the re-establishment of normal neuromuscular transmission and potential cure of the disease.
Nancy Law Impact Award
Xin-Ming Shen, Ph.D.
Mayo Clinic, Rochester, Minnesota
Amount Awarded: $100,000 over 1 year
Project Funded: The 3’ untranslated region variants and therapeutic targets in congenital myasthenic syndrome genes
Congenital myasthenic syndromes (CMS) are uncommon and incapacitating conditions that disrupt the communication between muscle and nerve at the neuromuscular junction. They often result in misdiagnoses and inappropriate treatments. Globally, researchers have identified 35 genes associated with CMS, but there are more to discover. Recently, we encountered CMS patients with alterations in the specific part of the gene region across three different genes that can impact protein expression. It is believed that there may be more such changes that remain undiscovered due to the complexities of their investigation. This project seeks to delve deeper into these genetic variations in CMS patients and to explore an innovative therapy approach involving the influence of these gene regions. This research has the potential to enhance the understanding of these rare conditions and uncover new avenues for assisting those who suffer from them.
Grant Cycle Details
In this grant cycle, MGFA expanded our eligibility criteria to accept letters of intent and applications globally, leading to more robust and exciting project and collaboration possibilities from diverse perspectives.
Recipients were selected from a record number of applicants representing scientists in Canada, Italy, Germany, Portugal, the Netherlands, Sweden, and the United States.
The research grants program at MGFA grew exponentially in 2023. MGFA more than doubled the amount of funding offered. In addition, the grant review process was aligned with NIH standards.
“We brought our policies and procedure for application, scoring and review into alignment with the standards of the NIH, and convened a study section of expert reviewers to ensure that MGFA funds contribute to the most meritorious research projects,” said Samantha Masterson, President and CEO of the Myasthenia Gravis Foundation of America.
Our grants program is part of the MGFA’s mission to enhance lives and improve care through scientific discovery.
Since our inception in 1952, we have led the charge to support the most promising scientific endeavors—funding research, engaging young scientists and clinicians, and spearheading a comprehensive patient registry. Research has led to significant improvements in diagnostic techniques, treatments and therapies, and improved disease management.
Learn more about the MGFA’s research agenda.
Recipient Biographies
About Ryan Hibbs
Ryan Hibbs studied chemistry and biochemistry at Whitman College, a small liberal arts college in Washington, graduating in 2000. He did his PhD research at the University of California, San Diego with Palmer Taylor from 2001-2006, and his postdoctoral research with Eric Gouaux at the Vollum institute from 2007-2012. He started his independent lab in 2012 in the Departments of Neuroscience and Biophysics at University of Texas Southwestern Medical School. He was promoted to associate professor in 2019. In 2023 he moved his research lab to University of California, San Diego where he is professor and vice-chair of the Department of Neurobiology and professor of pharmacology. His research focuses on the structure of brain and muscle receptors involved in fast chemical transmission, and how signaling of these receptors is modulated by drugs and disrupted in disease. A major emphasis in the lab is understanding the fine details of how autoimmune antibodies interact with these receptors to cause pathology. Past honors include Klingenstein and McKnight Scholar awards, the UC San Diego Outstanding Alumnus Award, and the Norman Hackerman Award in Chemical Research.
About Ricardo Maselli
Ricardo Maselli obtained his medical degree at the University of Buenos Aires, where he served as an undergraduate teaching assistant in the Department of Physiology. He completed his internship at University Hospital of El Paso Texas and his neurology residency at Queen's University in Ontario, Canada. He was a clinical and research fellow in clinical neurophysiology at the University of Chicago, where he later served as an assistant professor of neurology. He is currently the director of the Clinical Neurophysiology-EMG Laboratory and a professor of neurology at the University of California, Davis. He is a translational neurologist whose main research interests are congenital myasthenic syndromes (CMS) and gene therapy for CMS.
About Xin-Ming Shen
Xin-Ming Shen, PhD, FAAN, FANA, serves as an associate professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Shen obtained his doctoral degree from Shanghai Medical School, Fudan University, China, and completed a fellowship in the neuromuscular disease research program at Mayo Clinic. His research is focused on exploring the pathogenic mechanisms and therapeutics of neuromuscular diseases.