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!
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
C9 Biology Post
Search for a Self Cure # 1 TDP-43 Explainer
July 31st Talk with Dr. Seely
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
The Mystery of C9orf72
For many years, scientists thought neurodegenerative diseases were relatively straightforward. Abnormal proteins accumulated inside cells, became toxic, and then the neurons died. Today, researchers know the story is far more complicated.
In people with the C9orf72 repeat expansion, the mutation causes cells to produce abnormal RNA and proteins (7 kinds!). Scientists sometimes call this cellular "junk" because they accumulate over time and can clutter the cell's normal operations.
At the same time, another protein, TDP-43, begins to malfunction (the 8th type of junk). According to Dr. Seeley, one of the biggest shifts in the field has been recognizing that TDP-43 may not simply form toxic aggregates (“junk”). It also appears to lose some of its normal cellular functions. That distinction matters.
TDP-43 helps regulate a tremendous number of genes and cellular processes. When it stops doing its job correctly, the effects may ripple throughout the cell in ways researchers are only beginning to understand.
Why Understanding the Biology Matters: C9orf72
Dr Soto Albrecht recently sat down with Dr. Bill Seeley, a neurologist and researcher at the University of California, San Francisco (UCSF). Dr. Seeley has spent more than two decades studying why certain brain cells are vulnerable to ALS and FTD while others remain unaffected, like . His work has helped uncover key biological mechanisms that drive these diseases.
Their conversation focused on one of the biggest challenges facing researchers today: understanding exactly what is happening inside the cells of people who carry the C9orf72 mutation.
Why Different Diseases May Share the Same Biology
One of the questions that has driven Dr. Seeley's research is why ALS and FTD appear so different while often sharing the same genetic cause.
ALS primarily damages motor neurons, the cells responsible for controlling voluntary movement. FTD, by contrast, disproportionately affects specialized brain cells present in humans and some animals called von Economo neurons, which are involved in social behavior, empathy, emotional regulation, and complex decision-making.
For many years, scientists viewed these as fundamentally different diseases because they affected different neuron types. Dr. Seeley's work has helped show that motor neurons and von Economo neurons are actually more biologically similar than previously recognized. Although they serve very different functions, they appear to share characteristics that make them especially vulnerable to the disease process triggered by C9orf72 and TDP-43 dysfunction.
Understanding what these two neuron types have in common may ultimately help explain why the same genetic mutation can lead one person to develop ALS, another to develop FTD, and some individuals to develop features of both diseases. Rather than treating ALS and FTD as completely separate conditions, researchers are increasingly studying them as different manifestations of a shared biological process.
A Key Question: What Happens First?
One of the most intriguing findings from C9 research is that many abnormal RNA and protein products appear long before symptoms develop. Researchers can detect these changes years, and potentially decades, before someone develops ALS or FTD. They may even be with us our whole lives to some extent. So genetic carriers remain healthy during a time when they have seven types of junk accumulating in their cells, including neurons.
This raises a fundamental question: If these abnormalities appear so early, what triggers the transition from a healthy carrier state to disease development? Dr. Seeley described this as one of the most important unanswered questions in the field. He describes his study in which he found C9 aggregates in the temporal global of a C9-FTD patient a decade before symptom onset, and ponders this question.
Many researchers believe there is a shift at some point. The C9-related abnormalities have been present in the background, but something changes, and TDP-43 dysfunction begins to emerge. Once that happens, the disease appears to enter a more active neurodegenerative phase. (Of note: there is some nuance here. Some TDP-43 aggregates appear years/decades before the onset of the disease, and it even occurs with normal aging—so it is not black and white).
Understanding what triggers that transition could help researchers identify when to intervene, how to monitor disease progression, and potentially how to prevent disease before symptoms begin.
Not All "Junk" Is Created Equal
Developing treatments has been difficult because not all biological changes associated with C9 appear to have the same impact. Early studies suggested that many abnormal proteins appeared similar across different regions of the brain, leading some researchers to question whether they were truly driving disease.
However, more recent work suggests the answer may be more nuanced. Some abnormal proteins may be more harmful than others. Some appear more closely associated with TDP-43 pathology. Others may play a smaller role than originally suspected. Researchers are still trying to understand which biological targets matter most and when.
That uncertainty creates challenges for drug development, but it also highlights why continued research is so important.
Why Biology Matters for Treatment Development
For genetic carriers, it can be frustrating to hear that scientists are still debating the underlying biology.
After all, many people want treatments now for themselves and their loved ones.
But understanding the biology has real consequences for patients. Yentli pointed to a prior C9 antisense oligonucleotide (ASO) trial that targeted one aspect of the C9 mutation. The treatment ultimately failed and may have worsened disease progression in some participants. Researchers still do not know all the reasons for its failure.
However, experiences like this clinical trial reinforce the importance of understanding which biological processes should be targeted and which should not. The goal is not necessarily to understand every detail before developing therapies. But researchers need enough understanding to avoid targeting the wrong pathways or missing critical pieces of the disease process.
That same understanding depends on participation in research. Observational clinical studies allow scientists to follow individuals over time, helping identify the earliest biological changes that occur before symptoms begin. These studies provide an essential foundation for developing future treatments and prevention strategies. You can peruse observational studies you are eligible for at https://www.endthelegacy.org/recruiting-studies. Pay special attention to the national studies where your samples and data can be readily accessed by more scientists; these include ALL ALS, ALLFTD, ALS TDI ARC, and EverythingALS.
Researchers are also building new laboratory tools to better understand the disease. One example is the CureC9’s project developing a stem cell biorepository. Through this effort, skin samples donated by individuals with the C9 mutation can be transformed into induced pluripotent stem cells (iPSCs), which researchers can then develop into different types of neurons, including motor neurons (available now) and von Economo neurons (available some day!).
Studying these cells side by side allows scientists to investigate why some neuron types become vulnerable, how disease begins, and which therapeutic approaches may best protect them. A biorepository like this will enable scientists in industry and academia to study how these differ across C9 families for the first time. You can register interest in donating your skin cells to make C9 stem cells at https://curec9.com/projects/c9orf72-stem-cell-bank/.
Hope Comes from Momentum
Despite unanswered questions, Dr. Seeley remains optimistic. One reason is the field's extraordinary growth and the surge of energy and interest it has attracted.
When Dr. Seeley began studying ALS and FTD twenty years ago, many key genes, proteins, and vulnerable cell types had not yet been discovered. Today, researchers have a much richer understanding of the biology, and the field has attracted a new generation of scientists, clinicians, and biotechnology companies working to develop therapies. Dr. Seeley summed this up by saying, "The pace of progress during those 20 years, by scientific standards, has been blistering."
For genetic carriers, momentum in research matters and gives them a reason to hope. Every new discovery helps researchers refine their understanding of the causes of ALS and FTD, identify new therapeutic targets, and increase the likelihood that future treatments will be successful and could cure genetic carriers.
Why This Matters
For families affected by ALS and FTD, understanding the biology is more than understanding a disease. It is deeply personal. It is about understanding risk, identifying opportunities for prevention, and, ultimately, about survival.
Every person who participates in an observational study, donates biological samples, or contributes to efforts like the CureC9 stem cell biorepository plays a vital role in helping researchers get closer to understanding the roots of disease, why certain neurons are affected, and how future therapies might stop or even prevent ALS and FTD before any symptoms appear.
Researchers still do not know exactly what triggers the transition from healthy carrier to active disease. They do not yet know which biological changes are most important or which interventions will ultimately prove effective. But they are getting closer.
For Yentli, conversations like this are a reminder that progress is being made, even when it does not immediately lead to new therapies. The questions researchers ask are becoming sharper. The tools and technology are improving. And more people than ever are working to understand, treat, and ultimately prevent the disease.
