UCLA researchers in the Department of Medicine have identified the SV2 family of proteins as novel druggable targets for suppressing severe inflammation, including COVID-19 pneumonia.
Background: In critical COVID-19, the infection causes severe inflammation and excess fluid in the lungs, leading to breathing difficulties (COVID-19 pneumonia). Recent studies suggest that a damage-response cytokine, IL-33, may be involved in this immune hyper-responsiveness in the lungs of COVID-19 patients. IL-33 functions through its receptor ST2 to induce a type of innate immune cell called ILC2. Since ILC2s play crucial roles in various immune disorders and cancers, targeting the IL-33/ILC2 pathway could be a promising approach to manage COVID-19 pneumonia. However, no therapeutic drugs targeting IL-33 or ILC2s have been approved to date due to a lack of efficacy. Therefore, finding a novel druggable target for modulating the IL-33/ILC2 signaling is an urgent need to mitigate the devastating outcome of critical COVID-19 cases.
Innovation: Dr. Ke Shuai and colleagues in the UCLA Department of Medicine have identified synaptic vesicle glycoprotein 2 (SV2) as a novel druggable target for modulating IL-33 and ILC2, potentially allowing a new therapeutic for COVID-19 pneumonia. SV2 protein plays an essential role in seizure pathology and is the pharmacological target of anti-seizure drugs, such as FDA-approved levetiracetam (LEV). By utilizing genetically engineered mouse models, researchers have found that SV2 is also involved in immune regulation. Specifically, SV2 supports IL-33/ILC2 pathway by stabilizing ST2, the receptor of IL-33. In mice lacking SV2, IL-33 could not activate ILC2 reactions. More importantly, researchers have demonstrated that targeting SV2 effectively suppresses ILC2’s overactive responses in lung inflammation mouse model. Since LEV is FDA-approved (trade name: Keppra), drug repurposing could be a fast and promising strategy to test the efficacy of targeting SV2 in COVID-19 pneumonia, as well as other immune disorders and cancers.
Potential Applications:
- COVID-19
- Cancers
- Allergic disorders
Advantages:
- Repurposing of an FDA-approved drug
- Extensively characterized mechanism of action
Development to Date: The efficacy of LEV has been tested in mouse models. Targeting SV2 proteins by LEV suppressed lung inflammation in mouse models.
Related Papers (from the inventors only): Manuscript under review
Keywords: Cytokine, COVID-19, IL-33, SV2, Therapeutics, Immunomodulation, Levetiracetam (LEV), Anti-seizure, Drug repurposing, FDA-approved