Targeting CNS Expression of Chitinases as a Novel Therapy for ALS
Abstract
A well-known feature of amyotrophic lateral sclerosis (ALS) is the presence and activation of inflammation and inflammatory signaling pathways within the brain and spinal cord of patients. While increased inflammation is present in ALS patients, drugs that target inflammation have not proven effective in clinical trials. One reason is that most anti-inflammatory drugs target general features of inflammation and not key factors of inflammation that drive neuronal death. Another reason is that some types of inflammatory responses are actually beneficial and help keep cells alive and return or remain in a healthy functional status. A very big challenge is both identifying the good and bad inflammatory cells and signals, and to develop therapies that specifically target the bad inflammation and/or even promoting the good inflammation in ALS patients. We and others have discovered that a family of proteins called chitinases are expressed and released by specific cell types during inflammation and are present in high levels in cerebrospinal fluid of ALS patients. We recently discovered that these proteins are also present in the cells that control inflammation in nervous tissue. Thus, we propose that chitinases perform specific inflammatory cell signaling that in some areas contributes to good inflammatory signaling while in other areas of the brain and spinal cord induce bad inflammatory signals. With current technologies, it would be impossible to target the bad chitinase signals while preserving the good chitinase signals. In this project we will develop novel viral-based vector tools (adeno-associated virus or AAV) that target specific cell populations to either turn on or turn off chitinase gene expression. Through this method we will regulate the bad chitinase signals while preserving and expanding the good chitinase signals. We will test this therapeutic approach in the most commonly used mouse model of ALS, the mutant SOD1^G93A mouse model. However, this therapeutic approach is applicable to even the sporadic ALS population and therefore will have a high impact in treatments for ALS. At the end of this project, we will have viral vectors that target specific inflammatory cell types expressing chitinases in the human disease, and next steps will be to move this technology to testing in ALS patients. We will also further develop biomarker tests that measure each chitinase protein in human blood and cerebrospinal fluid. These chitinase biomarker tests will enable us to target our approach to specific ALS patient populations with high levels of chitinases and also to monitor the therapeutic impact of our viral vector-based treatments in blood and cerebrospinal fluid samples collected in ALS patients after treatment. This approach promises to be a novel therapeutic design that can be quickly moved into human clinical trials and also provides methods that can be beneficial for other neurodegenerative diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110144
Entities
People
- Robert Bowser
Organizations
- United States Army