CNS-Specific Disruption of Neuregulin Signaling to Stop Disease Progression in ALS
Abstract
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig s disease, is one of the most devastating and deadly neurological disorders for which we have no effective treatment. By the time a patient is diagnosed, the weakness is often localized to one region of the body, such as an arm or a leg. The disease then spreads relentlessly and often sequentially throughout the nervous system until the respiratory muscles are too weak to support life. While significant strides have been made in uncovering genes in a subset of patients with inherited forms of ALS, there are no genes or pathways that have been identified to block disease progression once it starts that could be used for all ALS patients, both familial (genetic) and sporadic. Our effort here is to advance a novel drug treatment that focuses on disease progression for all ALS patients. We have strong evidence in both human tissues from a wide variety of patients and one genetic animal model called SOD1 that the growth factor neuregulin1 promotes disease progression through activation of inflammatory and pathogenic microglial cells. We also have exciting results that we can slow or even stop disease progression by blocking neuregulin1 and this inflammation either through a genetic change in the animals or with a novel drug we developed called GlyB4. Here, we propose studies needed to advance GlyB4 toward clinical trials in patients with ALS. We will test whether blocking neuregulin1 in a second animal model will also slow disease progression, and prove that GlyB4 can block neureguiln1 in many types of human ALS stem cells. Since many drugs have failed clinical trials due to side effects, we will be giving GlyB4 directly into the brain cerebrospinal fluid (CSF) of mice and test its effects at different clinical stages of the disease: (1) At the beginning of the disease (onset, just after ALS is diagnosed in a patient) and (2) At the progressive stages of the disease. At each stage, we will show that the drug blocks neuregulin1 signaling, reduces microglial inflammation, and improves motor neuron structure and function. As part of this project, we will measure the activation of inflammatory microglial cells as a function of drug treatment. Based on many of our observations in human ALS tissues and animal models, microglial activation is an excellent surrogate biomarker of disease progression and reducing this inflammation will be a good biomarker of GlyB4 drug treatment. Based on the results here, we can then justify the use of a number of existing brain and spinal cord imaging methods (PET imaging) that specifically can measure microglial activation as an important biomarker that will help us run clinical trials of GlyB4. With these proof-of-concept studies, biomarkers studies, and other studies advancing GlyB4 drug development underway, we plan to launch phase I clinical trials in ALS patients within 5 years. The effects we have seen in ALS animal models with GlyB4 also occur in other animal disease models. After we advance GlyB4 for clinical use in ALS, we plan to target other diseases we have seen these similar effects including Alzheimer s, multiple sclerosis, and chronic pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310315
Entities
People
- Fei Song
Organizations
- United States Army
- University of Illinois at Chicago