From pTau217 to α-Synuclein: New Biomarkers Driving Neurodegeneration and Neuroinflammation Research

Alzheimer’s Disease, Multiple Sclerosis and Parkinson’s Disease are neurological disorders with devastating consequences for those affected and their families. These diseases are characterized by a lack of biomarkers specifically tracking disease progression and the effect of potential disease modifying therapies, leading to inadequate treatment possibilities and patient care.

In our recent webinar, “The Brain’s Breakdown: Biomarkers and ECM in Neuroinflammation and Neurodegeneration”, we invited world-renowned Alzheimer’s biomarker specialist Professor Charlotte Teunissen, Multiple Sclerosis treatment specialists Dr. Tobias Sejbæk and Nordic Bioscience’s Director of Neuroscience, Kim Henriksen, to share the current developments for biomarkers in neurologic diseases.

In Alzheimer’s Disease (AD), recently developed fluid biomarkers, such as phospho-Tau isoforms (pTau217), have shown the ability to predict disease progression and treatment response in both plasma and CSF (measured in our CAP/CLIA-certified lab). This clearly illustrates how far the neuro field has come and highlights the importance of such biomarkers or continuous drug development in AD.

For Multiple Sclerosis (MS) and Parkinson’s Disease (PD), the work focuses on identifying a panel of biomarkers reflecting different aspects of these complex diseases, including neuroinflammation, blood-brain barrier integrity and active neurodegeneration.

There are therapies and biomarkers available in MS, but we still lack refined biomarkers to monitor the ongoing efficacy of the drugs. Such biomarkers can be used to enrich patient populations with respect to responses, as well as supporting the development of new drugs. Biomarkers such as fragments of collagen type IV, which reflect turnover of the basement membrane of the blood-brain barrier, have shown promise.  

At the same time, in PD, there is a lack of biomarkers reflecting the underlying neuronal pathology especially in plasma/serum. Consequently, there is a competition on being the first to robustly detect the key protein α-synuclein—a biomarker that can capture the underlying pathology. Here, we introduced a novel assay detecting fragments of α-synuclein, which are generated during the loss of neurons. After further investigation, this biomarker could potentially become an important tool for drug development in PD.  

Overall, fluid biomarkers for neurodegenerative diseases have come a long way in the last decade and are clearly critical to the success of drug development trials.  

Quantification of active TGFβ in serum predicts treatment response in solid tumors

TGFβ signaling: a game changer in personalized cancer treatments?

Treatment outcomes are deeply influenced by the tumor microenvironment (TME) where TGFβ (Transforming Growth Factor Beta) has emerged as a critical factor that can dictate the success—or failure—of therapeutic strategies.

As shown below (Figure 1.) in an example from renal cell carcinoma (RCC), high TGFβ activity contributes to poor responses to tyrosine kinase inhibitors (TKIs) as compared immune checkpoint inhibitors. TGFβ activity was measured by the TGFβ-LAP biomarker in pre-treatment serum.

Conventional TGFβ assays are affected by platelets releasing TGFβ during clotting (drastically affecting the measurements in serum). In contrast, the TGFβ-LAP biomarker quantifies a cleaved latent activating protein (LAP) fragment which is independent of platelet TGFβ release providing a novel tool to indirectly measure TGFβ in serum.

Figure 1. TGFβ (Transforming Growth Factor Beta) has emerged as a critical factor that can indicate success rate

Why does this happen?

TKIs, such as Sunitinib, are primarily targeting angiogenesis and signaling pathways critical for tumor growth. However, elevated TGFβ promotes an immunosuppressive and fibrotic TME, counteracting these therapies by enhancing tumor resilience and protecting vasculature from the intended effects of TKIs. On the other hand, anti-PD-1/anti-CTLA-4 immuno-oncology (IO) therapies such as Nivolumab and Ipilimumab, which aim to re-activate T-cell responses, may be relatively more effective even in a TGFβ-rich environment.  

Personalizing treatment (TKI vs. IO) with biomarker-driven approaches

Understanding TGFβ activity could be a game-changer in personalizing cancer treatments. Biomarkers that measure TGFβ levels or its downstream effects might help clinicians choose between TKIs or immunotherapy – or even better, design combination regimens. This underscores the importance of a biomarker-driven approach to cancer treatments. As we continue to unravel these mechanisms, the goal remains clear: to turn the TME from a shield into a target. 

Our approach is designed to be implemented into clinical trials and research programs on TKI vs. IO, and to help explore the intersection of TGFβ biology and therapeutic resistance.

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