By Jonathan Brotchie

I recently had the opportunity to attend and share some of Atuka’s research at the 7th Annual Neuroimmunology Drug Development Summit in Boston. This meeting brought together over a hundred biotech and pharmaceutical leaders, all intent on unlocking the therapeutic potential of neuroinflammatory mechanisms for conditions such as Parkinson’s disease, Alzheimer’s, Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and more. Below, I share what were the most significant insights I gathered from the outstanding talks by experts in the field.

In overview, while both the innate and adaptive arms of the immune system appear to contribute to Parkinson’s pathology, in terms of therapeutic development most of the interest to date has focused on, and continues to focus on, the innate system. Of course, when it comes targeting the innate system, NLRP3 has been one of our hottest targets over the last 5 years. But where next?

TREM2, a membrane glycoprotein crucial for microglial survival, activation, phagocytosis, brain homeostasis, and the inflammatory response to injury or neurodegeneration, is emerging as one of the most promising new targets for Parkinson’s, both in terms of mechanism and the variety of approaches we have to potentially manipulate it.  Could it be the new NLRP3? Encouragingly, the spotlighting of TREM2 is validated by the recent announcement by The Michael J. Fox Foundation for Parkinson’s Research about its Targets to Therapies initiative. The big issue for me is how can we leverage our understanding of the role of the adaptive immune response in PD and expand our focus from the innate system.

At Atuka we’ve already been thinking a lot about TREM2 and we’re not alone. The rationale for an application in Parkinson’s is very solid and based around our growing understanding of the role of microglia in PD. Certainly, Microglia are crucial in the CNS, shifting to active, neuroprotective states when needed. TREM2 acts as a gatekeeper for this switch, responding to pathologies such as synuclein aggregation. There has been much focus on TREM2 in Alzheimer’s and several therapies have entered clinical development. Recent efficacy readouts include the Alector TREM2 agonistic antibody (AL002). While unfortunately failing to meet primary efficacy endpoints in Alzheimer’s (see the press release) has helped us learn much about the target. It’s clearly important to think about optimal therapeutic approaches to targeting TREM2. Small molecules might be better than antibodies as antibodies could be “captured” by soluble TREM2 acting as a sink and that could be a challenge to efficacy.

Each of the talks I heard took a different approach to engaging TREM2, each with pros and cons, but I really like the fact that we have multiple modalities available as we try to figure out how to optimally engage TREM2.

1. David Gray (Vigil Neuroscience) – TREM2 Modulation for Genetically Defined Microgliopathies

David Gray’s session highlighted Vigil Neuroscience’s strategic approach to TREM2.

• Rare disease and Alzheimer’s: Vigil’s pipeline splits between an antibody program targeting ALSP (Adult-onset Leukoencephalopathy with axonal Spheroids and Pigmented glia) and a small-molecule program for Alzheimer’s disease.

• ALSP insights: David explained how activating TREM2 can counteract CSF1R mutations, restoring microglial function.

• VG3927 in Alzheimer’s: Having recently completed Phase 1, this small-molecule TREM2 agonist bypasses many limitations of antibody therapies by avoiding the “soluble TREM2 sink,” offering more consistent microglial engagement.

My takeaway: The way Vigil tailors separate strategies for rare conditions and more prevalent neurodegenerative diseases demonstrates how flexible TREM2 targeting can be. The findings also highlight how microglial modulation might generalize to other CNS pathologies. It’s interesting that Vigil has both antibodies and small molecules. In the Alector antibody study, ARIA were reported, as has been seen with amyloid-beta antibodies, implying that ARIA are not related solely to amyloid-beta clearance or efficacy. Would ARIA be seen with small molecule TREM2 activators as well as antibodies?

2. Fabrizio Gasparini (Novartis) – TREM2 Modulation as an Anti-Inflammatory Approach to AD

Fabrizio shared Novartis’s progress with VHB937, an antibody that stabilizes TREM2 at the microglial surface, boosting its signalling potential.

• Mechanism of action: By preventing TREM2 shedding, VHB937 enhances microglial chemotaxis and phagocytosis, fostering improved remyelination in animal models.

• Clinical development: While VHB937 is being explored for ALS, Fabrizio also touched on its potential for Parkinson’s, citing an MPTP mouse study that revealed protective effects on dopaminergic neurons.

• Wider perspective: These data further support TREM2’s therapeutic relevance across the neurodegeneration spectrum, not just in Alzheimer’s.

My takeaway: Although TREM2 research is often discussed in the context of AD, Fabrizio’s mention of dopaminergic neuron protection suggests a broader role—one that I hope could inspire more interest in diseases like Parkinson’s.

3. Manuela Polydoro (Muna Therapeutics) – Small-Molecule TREM2 Agonists in Alzheimer’s

Manuela’s talk, which focused on the context of late-onset Alzheimer’s, shifted the spotlight to a small-molecule TREM2 activator that could circumvent some limitations of large-molecule therapies.

• Mechanistic details: Muna’s lead compound (MTX96943) dimerizes TREM2 and DAP12, improving microglial surveillance of lipids, debris, and neurotoxic aggregates. Crucially, it doesn’t get neutralized by soluble TREM2.

• Preclinical validation: In a 5xFAD mouse model, a pretty aggressive AD model, MTX96943 diminished amyloid loads and rebalanced microglial states, suggesting wide-ranging benefits beyond mere plaque clearance.

• Clinical plans: Manuela noted that Phase 1 trials are set to soon kick off, aiming to achieve robust engagement of microglia while minimizing adverse effects.

My takeaway: Muna’s small-molecule approach underlined a theme repeated throughout the conference, that TREM2 modulation is gaining momentum, and multiple avenues—antibodies, small molecules—may converge on a similar goal of harnessing microglia to combat neurodegeneration. We need to see these approaches more in PD.

The last talk I ‘d like to highlight was on a completely novel target and one I had not thought about before for Parkinson’s, Bruton’s Tyrosine Kinase (BTK).

4. Brian Hopkins (Biogen) – BTK Inhibitors for Autoimmune and Neurological Disorders

Brian Hopkins captured my attention with an update on how Bruton’s Tyrosine Kinase (BTK) inhibitors might transform both autoimmune and neurodegenerative disease treatments.

• Mechanism and rationale: Brian underscored BTK’s role in bridging B-cell receptor signaling to broader immune pathways—particularly relevant for MS.

• Lead compound (BIIB-091): In preclinical trials, Biogen’s inhibitor demonstrated potent and selective BTK blockade. Phase 2 studies in MS are ongoing, with potential applications across other neuroinflammatory conditions.

• Implications for Parkinson’s: If B-cells and myeloid cells shape PD pathology as they do in MS, BTK inhibition could open new therapeutic doors in Parkinson’s.

My takeaway: I was really taken by Brian’s passion for this target. He has been working on BTK for nearly as long as I have been in the PD space. Although BTK is more established in MS, Brian’s talk sparked ideas about how these same immunological pathways might influence PD. For instance, could BTK inhibition attenuate TLR2/4 driven cytokines production in the innate system, reducing impact of TNF-α, IL-1β, IL-6, all of which have been implicated in PD. Many questions flow from this one, about brain accessibility and systemic immune suppression, but it’s great to think about new possibilities for indication switching. Continued investment in BTK inhibitors for CNS disorders is clearly going to happen and let’s hope it creates new opportunities for partnership in Parkinson’s disease.

5. My talk (Atuka) – Neuroinflammation in Parkinson’s disease

In my own session I spotlighted the evolving paradigm that neuroinflammation plays a central, if not fully understood, role in PD progression.

• Innate and adaptive immunity: Microglial activation (or, perhaps more accurately, shifting microglial states) and T-cell involvement appear to be important immune drivers of PD pathology, echoing observations in other neurodegenerative diseases.

• Alpha-Synuclein models: I described how rodent models that overexpress or misfold alpha-synuclein replicate many of these immune responses, offering a robust platform to test immunomodulatory therapies.

• Collaborative opportunities: My principal aim was to encourage the neuroimmunology community to consider PD as an indication and encourage them to apply these models to validate and refine potential PD treatments—a space often overshadowed by Alzheimer’s and MS.

My takeaway: After chatting with fellow attendees, I sense growing curiosity about how PD might fit into the broader neuroimmunology landscape. I also saw great potential for the use of our aSyn models for therapeutic development across the field. The challenge (and opportunity) lies in adapting the promising strategies already underway in AD and MS to Parkinson’s research.

Please message me, or reply in the comments, if you would like to have a look at the deck from my talk.

Final Thoughts

The 7th Neuroimmunology Drug Development Summit underscored a dynamic shift in how we approach neurological disorders—emphasizing microglia, TREM2, and other immune pathways, such as BTK, as high-value therapeutic targets. Again, the recent announcement by the Michael J. Fox Foundation of its T2T initiative gives the spotlighting of TREM2 some welcome validation. And overall, the event served as a welcome reminder that while many neuroimmunology efforts currently center on Alzheimer’s disease, this same biology could have profound implications for Parkinson’s.