The Development of an Astrocyte Hemichannel Blocker to Delay Spatial and Temporal Progression in ALS
Abstract
The mechanisms by which disease progresses in ALS, both anatomically and over time, are unknown. Not being able to advise ALS patients regarding how their functional status may change in upcoming weeks or months is a serious challenge for patients, their caregivers, and physicians. Another significant challenge is that because most ALS patients seek medical care after they have developed some disability, the disease process, including death of motor neurons is already underway. In light of this, halting or slowing disease progression after disease onset, when patients are typically diagnosed, would offer enormous practical therapeutic potential. A consistent theme in our understanding of disease progression, after onset, in ALS suggests that astrocytes play a role in this disease progression. Our most recent work implicates the astrocyte connexin, Cx43, as a mediator of motor neuron (MN) toxicity using ALS mouse modeling of cells in a dish. Connexin 43 is a protein that can either form a pore (gap junction) that connects two cells together or a pore from the cell to the extracellular environment (hemichannel). We believe that the network of astrocytic hemichannels (HC), composed of connexin 43, may modulate the spatial and temporal progression of disease which ultimately results in MN death or dysfunction. Therefore, modulating Cx43 HC may be an excellent target for an ALS therapy. Tonabersat (SB-220453), a novel cis benzopyran derivative, was selected for its effect in moderating abnormally high levels of neuronal excitability. In addition, it was shown to antagonize a phenomenon called "cortical spreading depression" in part related to a reduction in nitric oxide release. Based upon this theory and preclinical results, tonabersat underwent study in phase II clinical trials as a prophylaxis for migraine. Tonabersat was shown to have a preventive effect on attacks of migraine aura. Because tonabersat can be taken by mouth and is well-tolerated by patients with few side effects, it is a drug that could be used in other diseases like ALS. Tonabersat has been shown to block Cx43 hemichannels in several studies, and this hypothesis provides the foundation for this program. First, this proposal will utilize several strategies to help us understand the importance of Cx43 HC in ALS disease progression. We will accomplish this by using human induced pluripotent stem cells (hiPSC) from ALS patients. By making these hiPSC into astrocytes (hiPSC-A) or motor neurons (hiPSC-MN) we can begin to understand how Cx43 HC from ALS patient astrocytes influence motor neuron death. We can do this in a dish. Because we can use hiPSC from many different ALS patients with different forms of ALS and with different rates of disease progression, we can begin to tease out how Cx43 HC play a role in these key ALS outcomes. In order to begin treating ALS patients with tonabersat, we also need to understand its effect in an ALS mouse model. Therefore, we will dose ALS mice with several different concentrations of tonabersat to see how it is distributed in the brain, the level that produces the fewest side effects, and also measure whether tonabersat can help slow or stop the progressive weakness that these ALS mice develop. Finally, this proposal will investigate whether the Cx43 protein can be a biomarker of disease. Because we know that we can measure this protein in brain tissues as well as cerebrospinal fluid (CSF) from ALS patients, we will investigate the relationship of Cx43 with the temporal progression of ALS to help us understand which patients might be most responsive to our drug. Based upon the known data using tonabersat in patients with migraine, we believe that if the proposal demonstrates that tonabersat works in our ALS animal models and human astrocyte/motor neuron cultures, a rapid filing of an FDA IND could be achieved within a two-year time frame. The Johns Hopkins University Drug Discovery program ha
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010161
Entities
People
- Nicholas J Maragakis
Organizations
- Johns Hopkins University
- United States Army