Understanding the NLRP3 PET Tracer and Its Potential Impact on Parkinson Disease Treatment

Marcelo Bigal, MD, PhD

Therapeutic inhibition of NLRP3, a member of a family of proteins known as inflammasome receptors, has the ability to prevent the innate immune system activation that follows the formation of the NLRP3 inflammasome. In research, aberrant activation of the NLRP3 inflammasome is known as a key driver of disease pathology in several neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS).¹

In recent news, a $150,000 grant from the Michael J. Fox Foundation has been awarded to Ventus Therapeutics for its Novel PET Tracer Development Program in PD research. The program supports development and validation of PET imaging techniques utilizing radiotracers of targets related to PD, such as NLRP3. The company will use the grant to focus on an NLRP3 PET tracer which will hopefully deepen the scientific community’s understanding of NLRP3’s role as a central driver of neuroinflammation.²

Marcelo Bigal, MD, PhD, chief executive officer of Ventus Therapeutics, sat down in an interview with NeurologyLive® to talk about how inflammation contributes to the progression of PD, and the role that NLRP3 plays in this process. He also talked about the challenges in demonstrating the blocking of NLRP3 and its potential therapeutic effects in PD. In addition, Bigal spoke about how the recent advancements in PET tracer development and the understanding of NLRP3 structure has paved the way for more sophisticated approaches for PD treatment.

NeurologyLive®: How does inflammation contribute to the progression of Parkinson's disease, and what role does NLRP3 play in this process?

Marcelo Bigal, MD, PhD: As we follow the recent developments in AD and PD, it's very difficult to measure delay in the progression of neurodegeneration in a short period of time because there are 2 antagonistic forces. While patients are progressing in the disease, clinicians are trying to induce improvement or decrease the progression. It’s difficult to disentangle these in a short period of time. Therefore, we often use research biomarkers, and, until recently, we did not know exactly what we were trying to understand by using these biomarkers.

There has been a lot of data recently in PD, with over 250 papers showing that inflammation is the driver of neuronal loss. But what type of inflammation? Acquired inflammation? Innate inflammation? First response? We believe that the driver is NLRP3, which is a sensor of cellular health in the microglia surrounding the neurons. NLRP3 senses cellular health, and it is activated by Tau and synuclein, which accumulate as part of the Parkinson disease pathophysiology. The activated microglia following NLRP3 sensing triggers an innate immune response that ends up damaging the neurons.

If that's the case, blocking NLRP3 should translate into improvement of PD progression and symptoms. The fundamental question, however, is how can we demonstrate that we are blocking NLRP3 within the cell? By developing a tracer that will bind to activated NLRP3, label it, and allow us to take a picture of the image. Once we demonstrate that there is a lot of inflammation that is related to NLRP3, we can give NLRP3 inhibitors to see if we can antagonize it. That's the philosophical approach of this project. The Michael J. Fox Foundation acknowledged the importance of this approach by launching the PET Tracer Development Program for a variety of disease-relevant targets, including NLRP3.

How do PET tracers provide a valuable tool for testing the hypothesis of NLRP3-mediated inflammation in Parkinson's disease?

You do not need to convince neurologists that PD matters and poses many challenges for treating motor symptoms, ON and OFF state, and gait symptoms. Neurologists are easily aware that levodopa, which is a standard of care, can cause dyskinesia and adverse events. However, I think that many neurologists, who are not movement disorder specialists, might not be aware of the role of inflammation. There's a lot of analogies between PD, AD, and ALS. The main analyses are driven by the fact that they all accumulate what we call toxic proteins, such as amyloid, synuclein or tau, but these proteins are, in reality, not toxic, they are misfolded.

These proteins are markers of disease and they're drivers of inflammation. But in any case, inflammation increases neuronal activity, including in those suffering dopamine dysfunction. In the case of PD, neurons are more likely to fire differently. In other words, inflammation adds to the inherent dysfunction, the neurons get hyperexcited and this translates into symptoms. I think the fundamental thing about inflammation is, regardless of the source, inflammation is symptomatic. If you have inflammation in your finger, your finger hurts. If you have inflammation in your skin, your skin gets red. If you have inflammation around your neurons, your neurons will react. In the case of PD, the consequence is progression of the disease and symptoms. If the neurons are reacting a lot, the patients are shaking more, the patients are having more problems in their gait, they are progressing and the neurons are dying at a higher rate.

The neurologist might think and say, “if that was the case, I could treat PD with Advil, an anti-inflammatory medication, or steroids.” That's when it comes to the point, we're talking about a very specific form of inflammation driven by innate immunity. In reality, it's not acquired, it's born with you and driven by NLRP3. That’s the beauty of PET tracers, because now we have the ability to test this hypothesis. There are monogenic animals that support this hypothesis and we also have preclinical models that support it. But what we didn’t have is the ability to measure the density of NLRP3 in the brain of humans - if NLRP3 correlates with inflammation in the human brain, and if the inflammation improves after you've inhibited NLRP3 with drugs. We are going to finally test this, thanks to The Michael J. Fox Foundation and academic centers in the US and elsewhere.

How have recent advancements and the understanding of NLRP3 structure paved the way for more sophisticated approaches to PD treatment?

I think we are in the break of disruption for PD, AD, ALS, and Huntington disease. Sometimes we get a little demotivated as clinicians because it seems that this has been coming a long way and is often not profoundly affecting the care. I like to mention that this is how it typically goes. Think about how everybody's super happy and super engaged in the treatment of obesity. Twenty years ago, obesity was a story in the making, there were so many medications that failed. Obesity was not even recognized as a disease, it was a cosmetic effect for many years. I'm very optimistic about the treatment of PD and the reason is we now understand the disease, which is the first step. We now understand the role of what I like to call ‘the magnifiers of the disease’ in regard to inflammation. Now, we know what part of inflammation we were talking about.

Here in my company, we have these structure crystals of NLRP3. For the first time, we have brain penetrant NLRP3 antagonists. Now we're going to have PET tracers for NLRP3 and other targets in PD. When the stars align, eventually the disruption comes. I'm very optimistic that the stars are getting very close to align, and I’m happy to be part of the story.

Transcript edited for clarity.

REFERENCES
1. Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262. Published 2015 Nov 5. doi:10.3389/fphar.2015.00262
2. Ventus Therapeutics Awarded Grant by The Michael J. Fox Foundation to Support Development of a NLRP3 PET Tracer. News Release. Ventus Therapeutics. April 20, 2023. Accessed May 15, 2023. https://www.ventustx.com/news/ventus-therapeutics-awarded-grant-by-the-michael-j-fox-foundation-to-support-development-of-a-nlrp3-pet-tracer/