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. Dr Soto Albrecht has recently launched a home for her research projects with Everything ALS at CureC9.com - we are all rooting for her!
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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 #3 - Penetrance
Search for a Self Cure # 1 TDP-43 Explainer
May 1st C9orf72 Biology 101
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
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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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Loss-of-Function vs. Gain-of-Function
A central question in C9orf72 research is whether the disease is driven more by what is missing from the cell or by what has been added.
Scientists often describe this using two concepts:
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Loss-of-function refers to the reduced or absent activity of a protein that normally plays a vital role in the cell.
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In C9orf72 biology, separate from the C9 repeat expansion, two C9orf72 normal proteins are made, which play important roles in the cell. If their production or levels are reduced by the presence of expanded and repeated C9 DNA, this is C9orf72 loss-of-function and may contribute to disease
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In TDP-43 biology, which is also at play in people with the C9 repeat expansion, TDP-43 has an important role in the cell called “alternative splicing” (see Episodes 1 and 2). When it’s not doing its job in the nucleus, this is TDP-43 loss-of-function and may contribute to disease
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Gain-of-function refers to harmful activity that should not occur within the cell. This is explained in detail below. Briefly:
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In C9orf72 biology, two toxic RNAs and five toxic proteins are made from the C9 repeat expansion DNA and accumulate into “junkyards” across the cell
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In TDP-43 biology, TDP-43 can accumulate in the cytosol into a junkyard. In the C9 repeat expansion, this is an 8th type of toxic buildup, usually appearing later in a genetic carrier’s life. In C9orf72-related ALS and frontotemporal dementia (FTD), both processes may occur simultaneously.
Many researchers believe that both loss-of-function and gain-of-function are likely involved.
This distinction is important because it influences how treatments are designed. A therapy that targets only one mechanism may be insufficient if both contribute to the disease.
Understanding C9orf72 Repeat Expansion: Why It Matters for Treatment
Yentli Soto Albrecht is an MD-PhD student at the University of Pennsylvania who carries the C9orf72 genetic mutation. Last year, she lost her father, Frank Albrecht, to C9orf72-related ALS after a rapid progression of just 14 months. She was with him during his final moments, facing the reality that she carries the same gene associated with this devastating disease.
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Yentli focuses her work at the intersection of medicine and research. If this genetic risk is part of her future, she wants to understand it clearly and contribute to scientific efforts to cure it. As a community scientist liaison with End the Legacy, she is dedicated to translating complex scientific concepts into language that patients, families, and genetic carriers can better understand.
One area that remains both important and challenging to grasp is the underlying biology of the C9orf72 repeat expansion.
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What the Repeat Expansion Does Inside the Cell
The C9orf72 repeat expansion introduces abnormal genetic material into the cell.
To understand its effects, it helps to revisit a basic concept in biology:
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DNA stores genetic information in the nucleus, the “safe”;
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RNA carries that information away from storage to be “read” into protein
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Proteins, or “buildings,” are produced from RNA in the cytosol and carry out most cellular functions
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In C9orf72, this system is disrupted. The repeat expansion acts like genetic “gibberish” that should not be present. In addition to producing normal components, the cell generates abnormal RNA and protein products that accumulate and interfere with normal function.
The Eight Key Contributors to C9 gain-of-function or the "Eight Types of Trash"
Researchers describe the products of the C9orf72 repeat expansion as toxic buildup within the cell. There are eight key contributors:
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Two (2) types of abnormal RNA, made from the C9 repeat expansion DNA
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Five (5) types of abnormal proteins (dipeptide repeat proteins, or DPRs), made from the C9 repeat expansion RNA
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One (1) additional protein, TDP-43, which becomes mislocalized, builds up, and toxic
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Together (2+5+1=8), these factors create multiple layers of disruption. The abnormal RNA and proteins represent gain-of-function, while the loss of normal protein activity contributes to loss-of-function.
Why Understanding Complicated Biology Matters for Treatment
These biological processes do not occur in isolation. As toxic RNA and proteins accumulate, normal proteins stop functioning properly, and cellular systems become overwhelmed. Researchers must identify which processes are most significant and how to target them safely, avoiding any unintended consequences.
Past experiences indicate that a fundamental understanding of C9orf72 biology is essential. In SOD1 ALS, antisense oligonucleotides (ASOs) are used to target RNA, preventing harmful protein production and demonstrating treatment success. A similar strategy was tested for C9orf72; however, the repeat expansion produces multiple types of RNA ((+) and (-) sense), and early approaches focused on only one type (+). This may explain why the treatment was ineffective, did not reduce all the C9 DPRs, and, in some cases, even accelerated disease progression.
This highlights the importance of understanding biological mechanisms before developing effective treatments.
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What Comes Next
Researchers are continuing to study how these mechanisms interact and how to target them safely. Key questions include:
How can toxic buildup be reduced?
How can normal functions be restored?
Can both gain- and loss-of-function be addressed simultaneously?
These questions are central to ongoing efforts to develop effective treatments.
What Is CureC9?
After one year of traveling the globe to attend neurodegeneration conferences, Yentli convened a Scientific Advisory Board of the most innovative C9orf72 scientists she admired with the singular goal to meaningfully alter C9orf72 disease. They meet 3-4 times annually and identify projects that hold promise to move the needle on treating C9 ALS and FTD, with the secondary objective of preventing C9 disease. This effort lives as the CureC9 Program within EverythingALS. To join these efforts, visit CureC9.com.
Why Genetic Carrier Participation Is Critical
To better understand c9orf72 biology 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.
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