Search For A Self Cure
Updates From Dr. Yentli Soto Albrecht
Series Description
In this series of videos, we will cover topics in molecular biology that are important to understanding pioneering ALS and FTD research. We will also present interviews with the clinicians and scientists leading these efforts! The series is presented by Dr. Yentli Soto Albrecht. Dr. Soto Albrecht is a C9orf72 repeat expansion carrier, an MD/PhD trainee at the Perelman School of Medicine at the University of Pennsylvania, the founder of PennMed Trainees Against ALS and FTD, the inaugural End the Legacy Community Science Liaison Fellow, and a fierce advocate for the community affected by inherited and sporadic forms of ALS and FTD.
2-17 -26 Phil Wong Interview: TDP-43 Biomarkers and Therapy Development
Credits:
Created by: Yentli Soto Albrecht, PhD
Visuals and editing: Kaylee Morris
Music and audio: Andrew Yarovenko
Video: Brooke Emmerich
Blogpost: Amanda Salisbury
Supported by PennMed Trainees Against ALS/FTD, the End the Legacy Community Science Liaison Fund, EverythingALS, and Corsalex
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Combination Strategies: Fixing the City from Multiple Angles
TDP-43 regulates thousands of RNA targets. When it fails, many systems break down. Some researchers are taking a complementary approach: instead of restoring TDP-43 broadly, they are targeting specific downstream proteins affected by its loss. One example is UNC13A, a major TDP-43 target now heading into early-phase clinical trials. This raises an important possibility: combination therapy. One drug may restore broad TDP-43 function, while another stabilizes key vulnerable targets. Together, they may be more powerful than either alone.
Why Genetic Carrier Participation Is Critical
None of these advances would have happened without genetic carriers volunteering for research. They contribute longitudinal blood samples, lumbar punctures, MRI scans, and clinical assessments. These data sets, many collected over the past 5–10 years, are the foundation for developing and validating new biomarkers. To understand how early a biomarker changes, researchers need repeated samples (sometimes every three to four months) from presymptomatic carriers. That consistency allows scientists to distinguish real disease signals from normal biological fluctuation.
Importantly, it is possible to participate in most research studies without knowing your genetic status. If you do decide to test and are gene-negative, you contribute as a control. If positive, you help build the future of prevention. Progress in this field is deeply intertwined with community participation. Here is a helpful table summarizing some key studies for genetic carriers, and you can read a comprehensive list at
https://www.endthelegacy.org/recruiting-studies.
Why There Is More Hope Now Than Five Years Ago
When asked what gives him hope, Dr. Wong was clear: today feels different.
We now understand a potential central root cause (TDP-43 dysfunction), have biomarker strategies to detect it early, are developing therapies that target it directly, and are launching early-phase clinical trials. The shift toward pre-symptomatic intervention is especially powerful - it is being employed for SOD1 ALS (ATLAS), and on the horizon for other genetic causes and interventions. Instead of waiting for neuron loss, the field is moving toward identifying dysfunction early, and intervening before clinical disease manifests. There is still much work to do, however, for widespread prevention trials to become a reality.
Looking Ahead
Dr. Wong’s team aims to enter Phase 1 clinical trials for their gene therapy within approximately two years through collaboration with the startup Syndeo. We hope this video helps you interpret and follow the molecular biology schematics on display for this work. Other TDP-43–related strategies are currently enrolling. Now, clinical trials take time, but for the first time, the path from molecular understanding to prevention is visible. For families who have watched generations affected by ALS and FTD, that visibility matters. We are not where we need to be yet. But we are closer than we have ever been.
And that feels like real progress.
Blog Post Explainer
Blog Post Explainer
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What Has Changed in ALS and FTD?
From a patient’s perspective, treatments may not yet look dramatically different. But according to Dr. Wong, scientifically, the field has transformed.
The most important shift? Understanding TDP-43. (See a quick explainer on this from our first video in this series here.)
About 20 years ago, researchers discovered that TDP-43, a protein involved in processing RNA, is abnormally involved in both ALS and FTD. This was groundbreaking because it revealed a shared biological root between two diseases that once seemed clinically distinct. Over the past decade, scientists have clarified what TDP-43 actually does. In simple terms: DNA is the blueprint, RNA is the intermediate instruction manual, and proteins are the building blocks that carry out the work of the cell. TDP-43 helps interpret RNA correctly so the right proteins are made. When TDP-43 loses its function, the cell’s instructions become scrambled. Some essential proteins disappear. Other abnormal protein fragments, called cryptic exons, appear when they shouldn’t. Over time, this dysfunction leads to neuron death. This shift from observing symptoms to understanding root biology has opened entirely new therapeutic doors.
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A New Type of Biomarker: Detecting “Buildings That Shouldn’t Be There”
One of the most exciting developments from Dr. Wong’s lab is a blood-based biomarker that detects the loss of TDP-43 function.
When TDP-43 fails, abnormal RNA segments get included in proteins. These create new, abnormal protein fragments—essentially “buildings that shouldn’t be there.” Dr. Wong’s team developed antibodies that specifically detect these abnormal fragments in biofluids.
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Why does this matter?
Currently, a widely discussed biomarker in ALS is neurofilament light chain (NfL). Nfl is not specific to ALS; it can rise after head injury or other neurological damage, and its rise in relation to symptom onset for all but fast-progressing SOD1 carriers is still being nailed down.
A TDP-43–based biomarker could be more disease-specific, potentially detect dysfunction earlier, and help identify individuals before symptoms begin. Something even more remarkable is that this biomarker may be detectable from a simple blood drop. The long-term vision is something akin to a rapid test, usable in a regular doctor’s office. For genetic carriers, this could mean identifying disease activity years before symptoms, and enrolling in preventive clinical trials before irreversible neuron loss occurs.
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A Gene Therapy “Backup System” for TDP-43
Biomarkers are only part of the story. Dr. Wong’s lab is also developing a gene therapy targeting TDP-43 dysfunction directly.
Here’s the key insight: when TDP-43 loses function, the cell has no backup system, so the team designed one. Using an AAV (adeno-associated virus) delivery system, similar in concept to other gene therapies, they engineered a modified version of TDP-43 that retains the functional portion that correctly binds and regulates RNA, while removing the problematic portion that aggregates and forms toxic clumps. In other words, it’s a streamlined version that does the job without creating “junk.” The goal? A one-time treatment delivered through blood or spinal injection that provides long-lasting protection. In animal studies, the therapeutic effect lasts for the lifetime of the animal (though unfortunately the lifespan of lab animals is much less than that of humans, so this is taken with a grain of salt). Eventually, the vision is preventive use: delivering this therapy before significant damage occurs.
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Combination Strategies: Fixing the City from Multiple Angles
TDP-43 regulates thousands of RNA targets. When it fails, many systems break down. Some researchers are taking a complementary approach: instead of restoring TDP-43 broadly, they are targeting specific downstream proteins affected by its loss. One example is UNC13A, a major TDP-43 target now heading into early-phase clinical trials. This raises an important possibility: combination therapy. One drug may restore broad TDP-43 function, while another stabilizes key vulnerable targets. Together, they may be more powerful than either alone.
Why Genetic Carrier Participation Is Critical
None of these advances would have happened without genetic carriers volunteering for research. They contribute longitudinal blood samples, lumbar punctures, MRI scans, and clinical assessments. These data sets, many collected over the past 5–10 years, are the foundation for developing and validating new biomarkers. To understand how early a biomarker changes, researchers need repeated samples (sometimes every three to four months) from presymptomatic carriers. That consistency allows scientists to distinguish real disease signals from normal biological fluctuation.
Importantly, it is possible to participate in most research studies without knowing your genetic status. If you do decide to test and are gene-negative, you contribute as a control. If positive, you help build the future of prevention. Progress in this field is deeply intertwined with community participation. Here is a helpful table summarizing some key studies for genetic carriers, and you can read a comprehensive list at
https://www.endthelegacy.org/recruiting-studies.
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Why There Is More Hope Now Than Five Years Ago
When asked what gives him hope, Dr. Wong was clear: today feels different.
We now understand a potential central root cause (TDP-43 dysfunction), have biomarker strategies to detect it early, are developing therapies that target it directly, and are launching early-phase clinical trials. The shift toward pre-symptomatic intervention is especially powerful - it is being employed for SOD1 ALS (ATLAS), and on the horizon for other genetic causes and interventions. Instead of waiting for neuron loss, the field is moving toward identifying dysfunction early, and intervening before clinical disease manifests. There is still much work to do, however, for widespread prevention trials to become a reality.
Looking Ahead
Dr. Wong’s team aims to enter Phase 1 clinical trials for their gene therapy within approximately two years through collaboration with the startup Syndeo. We hope this video helps you interpret and follow the molecular biology schematics on display for this work. Other TDP-43–related strategies are currently enrolling. Now, clinical trials take time, but for the first time, the path from molecular understanding to prevention is visible. For families who have watched generations affected by ALS and FTD, that visibility matters. We are not where we need to be yet. But we are closer than we have ever been.
And that feels like real progress.
For families affected by ALS and FTD—especially those carrying genetic mutations like C9orf72—it can often feel like nothing has changed. Generations have watched loved ones face the same diagnosis, the same progression, and the same outcome. We don’t just want progress in theory; we want prevention, treatment, and hope in our lifetime.
In a recent conversation, our science liaison Dr. Yentli Soto Albrecht sat down with Dr. Phil Wong, a neuroscientist at Johns Hopkins University whose work has helped reshape how we understand ALS and FTD. What emerged was cautious but genuine optimism.
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