Imagine diagnosing ALS or frontotemporal dementia (FTD) through a simple blood test, before symptoms ever appear. That’s the bold vision behind a cutting-edge international research effort led by scientists at Novartis, in collaboration with DZNE, Oxford University, and KU Leuven. Their focus? Tiny, cell-derived particles called extracellular vesicles (EVs) that may carry the earliest and most reliable molecular clues of neurodegenerative disease.
These vesicles are like biological postcards, released by cells into the bloodstream and spinal fluid, and packed with proteins, RNA, and other cargo that reflect what’s happening deep inside the nervous system. If decoded correctly, they could help track one of ALS and FTD’s most elusive features: TDP-43 dysfunction.
| ALS 101: Extracellular Vesicles (EVs): Tiny bubble-like particles released by cells that carry proteins, RNA, and other materials, offering a snapshot of what’s happening inside the cells they came from. TDP-43: A protein that regulates how RNA is processed in cells. In ALS and FTD, it can mislocalize or become dysfunctional, contributing to disease. Phosphorylated TDP-43 (phospho-TDP-43): A modified form of TDP-43 that is commonly associated with disease and used as a marker of pathology. Cryptic RNA Transcripts: Abnormal RNA fragments produced when TDP-43 fails to properly regulate gene expression; these fragments are considered a hallmark of TDP-43-related disease.CSF (Cerebrospinal Fluid): The clear fluid surrounding the brain and spinal cord. It can be sampled to look for biomarkers of neurological diseases. Size Exclusion Chromatography (SEC): A method for separating particles (like EVs) based on size, used to purify samples for analysis. Immunocapture: A lab technique that uses antibodies to “capture” specific particles—like EVs with certain surface proteins—for more targeted analysis. L1CAM: A protein previously used to identify EVs coming from neurons, though its specificity is now under debate. Omics Data: Large-scale biological data sets (like genomics, proteomics, or transcriptomics) that help researchers understand complex systems like disease processes. Antisense Oligonucleotides (ASOs): Short synthetic strands of genetic material designed to correct or silence faulty genes—an emerging therapy in ALS and other neurological conditions. |
The Search for a Window into the Brain
TDP-43 is a protein that goes rogue in most cases of ALS and nearly half of FTD, disrupting how cells process genetic information. But until recently, there’s been no easy, reliable way to measure TDP-43-related damage in living patients. That’s where this consortium comes in.
By developing highly sensitive assays, some requiring only a few microliters of plasma, the team has shown that TDP-43 pathology is detectable in extracellular vesicles, specifically those enriched with cryptic RNA transcripts and phosphorylated TDP-43 protein. These biomarkers are especially promising because EVs are thought to preserve cargo from within cells, offering a more “intracellular” view than whole blood or CSF alone.
Refining the Toolkit: How to Best Capture EVs
Not all EVs are created equal and isolating the ones that matter most has become a science of its own. The team compared methods like size exclusion chromatography and immunocapture (which targets surface proteins on vesicles). Immunocapture appears especially effective, offering deeper protein analysis with less background noise.
One challenge remains: determining which EVs are truly from neurons. Many researchers have relied on a protein marker called L1CAM, but new data suggest it’s not always specific to the brain. Alternatives like NEXN3 and ATP1A3 may offer more precise targeting, and the team is exploring these options in parallel.
From Bench to Bedside: Clinical Translation in Motion
Thanks to longitudinal biofluid samples and omics datasets from Target ALS, the consortium can validate its findings across multiple labs and patient populations; an essential step in translating science into diagnostics. As Novartis’s Dr. Arti Patel explains:
“Target ALS is really fostering this collaboration with the access to longitudinal human biofluids and patient omics datasets. I think this is a valuable resource that is going to impact the success of our consortium.” – Dr. Arti Patel, Principal Scientist, Program Lead, Neuroscience, Novartis Institutes for BioMedical Research (NIBR)
The team is also exploring how TDP-43-related biomarkers in EVs change over time, how they might differ by genetic mutation or age, and whether they can predict disease progression. There’s even interest in testing EVs from patients who receive antisense oligonucleotide (ASO) treatments, to see if biomarker levels shift in response; an early clue that a therapy may be working.
💡 Key Takeaway
By detecting signs of disease before major symptoms arise, EV-based biomarkers could dramatically speed up diagnosis, monitor treatment response, and help match patients to the therapies most likely to help them. TDP-43 has long been one of ALS and FTD’s most frustrating blind spots. This consortium is helping to change that, turning invisible pathology into something we can measure, track, and target.
