Restoring Neuromuscular Junction Integrity to Alleviate ALS Progression
Abstract
ALS is a neuromuscular disease characterized by motor neuron death and muscle atrophy. The Centers for Disease Control and Prevention estimates that ~15,000 Americans have ALS. When breathing muscles become affected, ALS patients will need permanent ventilatory support. Most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first occur. Currently, there is no effective cure for the disease. About 5% to 10% of ALS cases occur within families, called familial ALS, while most cases of ALS are sporadic. However, both familial and sporadic ALS often exhibit oxidative stress, which reflects an imbalance between the production of free radicals and the ability of the body to counteract or detoxify their harmful effects with antioxidants. These oxidative stresses affect the patient s nerve and voluntary muscles to function normally, rendering them vulnerable to injuries. In May 2017, the FDA approved Radicava as the first-ever injectable drug to treat this devastating disease. In fact, Radicava is only the second drug ever approved for human ALS patients in 20 years (behind Riluzole). Radicava acts as a free radical scavenger and prevents oxidative stress damage to neurons, slowing down the decline of loss of function in ALS patients and can be administered intravenously. While treatment with Radicava will not cure ALS, slowing the decline of the loss of voluntary muscle function in ALS can improve the patients life quality. Pilot studies from our laboratory research have found that the ALS breathing muscle experiences exacerbated damages, which take place prior to the development of ALS symptoms. If we find a drug that can maintain and restore the integrity of the muscle and neurons, we may find a more effective way to treat ALS. A protein drug, MG53, was recently found to have the intrinsic capacity to repair injuries to the muscle cells and neurons. MG53 is present in our human body and constantly circulates in the bloodstream. Thus, MG53 can potentially be a safe biologic reagent to treat ALS. Since the discovery of MG53 in 2009, many advances have been made in understanding the biological function of this protein and in translating the basic findings into regenerative medicine applications. We can now produce and purify the recombinant human MG53 (rhMG53) protein in large scale. The rhMG53 can be stored as lyophilized powder and be readily dissolved in saline solution as an injectable drug. Testing with animal models shows that rhMG53 is safe when administered intravenously. Our objective with this project is to conduct proof-of-concept studies testing the efficacy and safety of this novel protein therapeutic in animal models of ALS. Fulfillment of the proposed studies, if successful, will pave the pathway for bringing rhMG53 into an FDA-approved drug that can be used to prevent or treat ALS. The proposed research will benefit military Soldiers, Veterans, as well as civilians with either familial or sporadic ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810684
Entities
People
- Jingsong Zhou
Organizations
- United States Army
- University of Texas at Arlington