Periodic Reporting for period 1 - MOBILISE (Monoamine oxidase B inhibitors as novel drugs targeting NLRP3 inflammasome)
Reporting period: 2020-09-01 to 2022-06-30
Although the number of anti-inflammatory drugs has increased during the past decade, there is still an urgent need to develop novel alternatives that overcome limitations of current treatments. The most used therapies, such as non-steroidal anti-inflammatory drugs, often present severe side-effects. In addition, biologicals have recently appeared, but they are extremely expensive. Therefore, novel therapeutic approaches with lower toxicity, higher tolerance and lower price must be developed to treat autoinflammatory and autoimmune diseases.
A key player in inflammation is the NLRP3 inflammasome, a cytosolic signalling complex that mediates the activation of potent inflammatory mediators. The excessive activation of the NLRP3 inflammasome is associated with the onset and progression of various diseases, including gout, pseudogout, metabolic arthropathies and multiple sclerosis. Therefore, targeting the NLRP3 inflammasome has the potential to provide therapeutic effect in a wide variety of inflammatory diseases.
We discovered a novel activation pathway to the NLRP3 inflammasome, which opens new opportunities to use an existing line of compounds for radically new medical indications. We discovered that the enzyme Monoamine Oxidase B (MAO-B) activates the NLRP3 inflammasome by means of ROS production, positioning MAO-B as a promising target to treat autoinflammatory and autoimmune diseases (Sanchez-Rodriguez et al, Cell Mol Immunol 2021). Given that there are several MAO-B inhibitors (iMAO-B) currently used in the clinic for treatment against Parkinson disease, the use of iMAO-B represents a major opportunity to develop new therapies at low risk and a fraction of the cost.
The MOBILISE project has assessed the technical and commercial feasibility of MAO-B as a novel target to treat gout, pseudogout and other NLRP3 inflammasome-driven diseases. To this aim, we tested the efficacy of clinical-grade iMAO-B in preclinical models of gout and pseudogout. Our findings show that the drugs were highly beneficial in these models, as they significantly dampened the levels of pro-inflammatory cytokines, decreased the recruitment of inflammatory cells and the swelling at the site of injury.
To address the commercial feasibility, we collaborated with a science and business consulting company. Its team of professionals supported us with their commercial skills and finally provided us a market report. Briefly, they do not recommend developing a novel iMAO-B drug (or a novel formulation), as it is a high-risk route, up to seven times more expensive compared to drug repurposing. They suggest that cross licensing iMAO-B with an iMAO-B manufacturer is a favourable commercialization route, also because the oral delivery of iMAO-B offers a strong value proposition. They also highlighted that developing iMAO-B for multiple chronic inflammatory diseases in parallel (e.g. gout, pseudogout and osteoarthritis) should increase the chances of success and spread the risks in clinical trials which is commonly done in general (e g basket trials). Several NLRP3 inhibitors in development also focus on different indications further validating this strategy.
A key player in inflammation is the NLRP3 inflammasome, a cytosolic signalling complex that mediates the activation of potent inflammatory mediators. The excessive activation of the NLRP3 inflammasome is associated with the onset and progression of various diseases, including gout, pseudogout, metabolic arthropathies and multiple sclerosis. Therefore, targeting the NLRP3 inflammasome has the potential to provide therapeutic effect in a wide variety of inflammatory diseases.
We discovered a novel activation pathway to the NLRP3 inflammasome, which opens new opportunities to use an existing line of compounds for radically new medical indications. We discovered that the enzyme Monoamine Oxidase B (MAO-B) activates the NLRP3 inflammasome by means of ROS production, positioning MAO-B as a promising target to treat autoinflammatory and autoimmune diseases (Sanchez-Rodriguez et al, Cell Mol Immunol 2021). Given that there are several MAO-B inhibitors (iMAO-B) currently used in the clinic for treatment against Parkinson disease, the use of iMAO-B represents a major opportunity to develop new therapies at low risk and a fraction of the cost.
The MOBILISE project has assessed the technical and commercial feasibility of MAO-B as a novel target to treat gout, pseudogout and other NLRP3 inflammasome-driven diseases. To this aim, we tested the efficacy of clinical-grade iMAO-B in preclinical models of gout and pseudogout. Our findings show that the drugs were highly beneficial in these models, as they significantly dampened the levels of pro-inflammatory cytokines, decreased the recruitment of inflammatory cells and the swelling at the site of injury.
To address the commercial feasibility, we collaborated with a science and business consulting company. Its team of professionals supported us with their commercial skills and finally provided us a market report. Briefly, they do not recommend developing a novel iMAO-B drug (or a novel formulation), as it is a high-risk route, up to seven times more expensive compared to drug repurposing. They suggest that cross licensing iMAO-B with an iMAO-B manufacturer is a favourable commercialization route, also because the oral delivery of iMAO-B offers a strong value proposition. They also highlighted that developing iMAO-B for multiple chronic inflammatory diseases in parallel (e.g. gout, pseudogout and osteoarthritis) should increase the chances of success and spread the risks in clinical trials which is commonly done in general (e g basket trials). Several NLRP3 inhibitors in development also focus on different indications further validating this strategy.