by Dr. Jonathan Brotchie

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A few days ago, Patrick Howson and I returned from the 6th Annual Inflammasome Therapeutics Summit in Boston, organized by our friends at Hanson Wade. 

It was encouraging to see just how mature and dynamic the inflammasome field has become, and how varied the potential indications are, from rare genetic disorders like Cryopyrin-Associated Autoinflammatory Syndromes (CAPS), through neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s, to common metabolic disorders like gout. 

Given Atuka’s primary areas of expertise, we were primarily there to learn more about the opportunities for inflammasome focused therapeutics in treating Parkinson’s, and welcomed the opportunity to share some of our data on the NLRP3 inflammasome. In our alpha synuclein models of PD, we have seen the powerful neuroprotective effects of inhibiting the NLRP3 inflammasome with the tool compound MCC950. It’s an area in which we’ve worked with many collaborators over the past five years, probably more than any other target in PD. 

(For anyone reading who doesn’t know much about NLRP3 inflammasome, I have included a brief overview of the biology toward the end of this post.)  

A real highlight was the talk from Matthias Geyer of the University of Bonn. Geyer is a structural biologist and is using nanobodies derived from camelids (llamas and alpacas) to help us better understand the structural biology of Gasdermin D pore formation. I’m always impressed with how that atomic-level understanding can give insight into how we develop therapeutics for this system.  

We were also excited to hear more about the programs Monte Rosa Therapeutics are pursuing. In an amazing talk from Alison Paterson, the company’s VP for Discovery Biology, we learned that Monte Rosa is developing a series of compounds, which they call molecular glue degraders, to disrupt the NLRP3-NEK7 interaction. They are essentially finding mechanisms to block inflammasome or NLRP3 inflammasome activity in a way that’s different from NLRP3 blockers like MCC950 et al, by disrupting the formation of inflammasomes.  

In a similar manner, disrupting assembly rather than directly blocking function of inflammasomes was the subject of the presentation by David Bearss from Halia Therapeutics. As Halia’s focus is very much on Alzheimer’s disease, we were surprised to see them targeting LRRK2; obviously, we’re very familiar with LRRK2 in Parkinson’s, but what the Halia group are proposing is very exciting—an LRRK2-Rab10-NLRP3 functional link in the assembly and subcellular distribution of the NLRP3 inflammasome. Certainly, we believe there’s an opportunity in Parkinson’s for the potential use of these types of molecules. Likewise, Halia are also developing NEK7 binding molecules which interact allosterically with the NLRP3 inflammasome, with the point again of stopping assembly. Making it another area of potential in Parkinson’s for molecules of that class. 

As Parkinson’s specialists, Davide Basco’s update of progress on AC Immune’s program to block NLRP3 activity was of particular interest. It seems that AC Immune has one of the strongest programs, small molecules and antibodies to different aspect of the inflammasome system. Davide shared data on one small molecule that was highly brain penetrant and directly interacts with NLRP3. Given that mode of action, it is, perhaps, one of the most obvious candidates to move forward, capitalizing on the data we’ve seen, as mentioned above, with MCC950—which is a great tool compound, even if it is clearly never itself going to be a drug, due to liver toxicity observed in Phase II clinical trials.  

Also on our radar in the realm of NLRP3 blockers was Ventyx, who continue to be leaders in this area, with both centrally acting and peripherally selective NLRP3 antagonists. Meanwhile, the presentation by Andrew Hamer of Cardiol showed the potential in cardiac conditions, such as persistent endocarditis, of that same class of molecules. We were also impressed by what we heard from Nellwyn Hagen of Sanofi, given the breadth of attention the company is clearly focusing on NLRP3 and neurodegenerative disorders, particularly apparent around their work related to Parkinson’s and ALS. The work that Nellwyn and her team have performed, looking at changes in gene expression in an in vitro system comprising of cultured neurons, microglia, and astrocytes and in acute and sub-acute MPTP models of Parkinson’s was especially interesting.    

Across many presentations, evidence accumulated showing inhibition of inflammasomes provides clinical benefit. Clinical data presented included effects in specific inflammasomopathies, such as CAPS, and pain associated with wisdom tooth extraction. Whilst these indications may not be the diseases for which these therapies are ultimately approved, the generation of positive proof-of-concept clinical data strengthens the hypothesis that inflammasome inhibition is both a safe and efficacious way of treating multiple diseases.

It was also interesting to hear more about other inflammasomes in addition to NLRP3, with Paul Ashton of Inflammasome Therapeutics presenting data on their NLRP3 / NLRC4 inhibitor and Feng Shao of Pyrotech Therapeutics presenting data on noncanonical inflammasomes. To date, we do not know if these inflammasomes are activated in our models of Parkinson’s disease and look forward to investigating the potential role of these inflammasomes to the neurodegeneration that occurs in our models. 

It was a great conference to be a part of, and Patrick and I appreciated the opportunity to share our NLRP3 data with the folks who were there. For once, I just wish I had more time to hang out in Boston—having gone without a single lobster roll on this trip. 

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On the Biology of the NLRP3 Inflammasome 

The NLRP3 inflammasome is a multiprotein complex that plays a key role in the body’s immune response by detecting and responding to harmful stimuli, such as pathogens, toxins, or cellular stress. It is part of the innate immune system, functioning to activate pro-inflammatory cytokines like IL-1β and IL-18. Upon activation, the NLRP3 protein oligomerizes and recruits ASC (apoptosis-associated speck-like protein containing a CARD), which in turn recruits pro-caspase-1. Once activated, caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature, active forms. 

Key Components of the NLRP3 Inflammasome: 

• NLRP3 (NOD-like receptor pyrin domain-containing protein 3): This sensor molecule detects a wide range of stimuli, including microbial infections, extracellular ATP, and crystalline substances like uric acid. Upon activation, it forms the core of the inflammasome. 
• NEK7 (NIMA-related kinase 7): NEK7 interacts with NLRP3 and is essential for inflammasome assembly. It acts as a scaffolding protein, facilitating the proper formation and activation of the NLRP3 inflammasome. 
• ASC (apoptosis-associated speck-like protein): ASC is an adaptor protein that bridges NLRP3 and pro-caspase-1, allowing the recruitment of pro-caspase-1 to the inflammasome. 
• Caspase-1: Caspase-1 is activated within the inflammasome and is responsible for cleaving pro-IL-1β and pro-IL-18, leading to their activation. It also cleaves gasdermin D, triggering pyroptosis (a form of inflammatory cell death). 
• Gasdermin D: Gasdermin D, once cleaved by caspase-1, forms pores in the cell membrane, leading to pyroptosis. This process releases intracellular contents, including mature IL-1β and IL-18, into the extracellular space, amplifying the inflammatory response. 
• KEF7: KEF7 has been identified as a negative regulator of the NLRP3 inflammasome, acting to modulate the extent of inflammasome activation and thus controlling the magnitude of the immune response. 

The assembly and activation of the NLRP3 inflammasome are tightly regulated, and dysregulation has been implicated in various diseases, CAPS, gout, recurrent pericarditis, Parkinson’s, Alzheimer’s, and other neurodegenerative conditions.