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.
Prior Topics
Search for a Self Cure # 1 TDP-43 Explainer
Search For a Self Cure # 2 Interview with Dr. Phil Wong on TDP-43 Biomarkers and Therapies
Search for a Self Cure # 1 TDP-43 Explainer
March 26 Understanding Penetrance: What Does Genetic Risk Really Mean?
Credits:
Created by: Yentli Soto Albrecht, PhD
Visuals and editing: Kaylee Morris
Music and audio: Andrew Yarovenko
Video: Brooke Emmerich
Blogpost: Izzi Rose Stern, Ed.D.
Supported by PennMed Trainees Against ALS/FTD, the End the Legacy Community Science Liaison Fund, EverythingALS, and Corsalex
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
What Is Penetrance?
Penetrance refers to the likelihood of developing a disease if you carry a specific genetic mutation.
In the case of C9orf72 repeat expansion, the gene can lead to amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or sometimes both. Penetrance is the probability that a person who carries this mutation will develop one of those conditions over the course of their life.
When Yentli received her genetic results in 2023, she was given risk estimates based on published research. She was told that the likelihood of developing ALS or FTD by age 55 was about 50 percent, and by age 65, the estimate increased to roughly 95 percent.
Those numbers can be difficult to process.
At the same time, she began hearing different figures from researchers at scientific conferences. Some studies suggested the lifetime risk for C9 carriers might be closer to 20 or 30 percent. Naturally, this raised an important question: how can both sets of numbers be accurate?
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Why Do the Numbers Differ?
One reason is that penetrance is not always the same across every family.
Population studies provide averages across many individuals. However, a person’s actual risk may depend on their family’s specific genetic background and environmental influences.
Looking at family history can sometimes provide additional clues. If most relatives who carried the gene developed the disease, penetrance within that family may be relatively high. If some relatives lived to older ages without symptoms, the penetrance may be lower.
In Yentli’s family, her father’s generation included three siblings. Two developed ALS, while the third has not been genetically tested. Based on that information alone, the penetrance in that generation appears to fall somewhere between roughly 70 and 100 percent.
While that estimate is not comforting, it does provide clarity about the risk her family may carry.
Yentli Albrecht is an MD-PhD student at the University of Pennsylvania and carries the C9orf72 genetic mutation. Last year, she lost her father, Frank Albrecht, to C9 ALS. She was with him in his final moments, facing the reality that she carries the same gene associated with the disease.
After his passing, Yentli took time to reflect on what she wanted to do next. Ultimately, she decided to focus even more deeply on the work she was already pursuing in medicine and research. If this genetic risk is part of her future, she wants to understand it as clearly as possible and contribute to scientific efforts to cure it.
One concept that initially confused her and continues to confuse many genetic carriers is penetrance.
How Should Carriers Interpret Genetic Risk?
Many people respond to conversations about genetic risk by offering reassurance. When newer studies suggest that penetrance might be lower than previously believed, some interpret that as a reason not to worry.
But genetic risk is rarely captured by a single number.
Published statistics represent large populations. Individual families may experience very different patterns. Understanding both the scientific data and one’s own family history can help carriers interpret those numbers more thoughtfully.
At the same time, risk does not equal destiny. Some carriers never develop disease, and understanding why is one of the most important questions researchers are now trying to answer.
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What factors protect certain individuals?
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What modifies risk?
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What might delay or prevent disease altogether?
These questions are central to ongoing research on ALS and FTD.
Why This Matters
Understanding penetrance helps shape how genetic carriers think about prevention, research participation, and long-term planning.
It also helps people interpret emerging scientific findings more carefully. When new research suggests that risk may be lower than previously thought, an important follow-up question is always: in which population?
For Yentli, recognizing that her family’s penetrance appears high has not led to resignation. Instead, it has provided focus. It is one of the reasons she continues to pursue research aimed at accelerating treatments and prevention strategies.
Penetrance may sound like a technical scientific concept. But for many families affected by ALS and FTD, it is deeply personal. Understanding it is one step toward changing what those numbers may mean in the future.
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Going In Detail on C9orf72 Penetrance
The C9 mutation was first identified in families with many members affected by ALS and FTD. In these families, the disease follows an autosomal dominant pattern — meaning if a parent has it, each child has a 50% chance of inheriting it. The disease risk in these families is high, and most people enrolled in research studies come from families like this.
After the mutation was discovered in those high-risk families, researchers also found it in some people with ALS or FTD who had little or no family history of the disease.
At first, scientists assumed the mutation meant the same thing regardless of family background. But over time, research has shown that people who carry C9 but come from families with little or no disease may actually have a lower risk than previously thought.
However — and this is important — that finding does not change the picture for families like Yentli's , where disease is widespread across generations. That risk remains high.
Why does the same mutation behave differently depending on family history? We don’t yet know.
Why Genetic Carrier Participation Is Critical
To better understand penetrance researchers need to study pre symptomatic carriers.
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.
