At the forefront of neurodegenerative research, Dr. Claire Clelland, John D French Alzheimer’s Foundation Endowed Chair, Assistant Professor of Neurology at the University of California, San Francisco, believes that for biologic therapies to move more swiftly into clinical trials, we need to involve the organism these options are designed to treat: human beings.
Clelland believes there’s a safe path forward to test potential therapies targeted at the central nervous system by tagging them with genetic barcodes that can show the route the particles take in human tissue on their way to a targeted organ or cell type. The goal is to remove genetic mutations, starting with leading genetic causes for FTD and ALS, and provide “a roadmap to cure other monogenic diseases over time.”
You can hear more from Dr. Clelland and her team’s transformative research from her talk in the DOC 2025 session, “Neurodegenerative Diseases: State of the Science and What You Can Do Now,” in our video, or read our lightly edited transcript below.
TRANSCRIPT:
Dr. Claire Clelland
I’m going to talk today about brain health, aging and what I think is the fastest path to curing dementia, which is through genetics. So I share the mission that many of you have in this room that we can cure neurodegenerative diseases, which is a disease, really, of aging. And I’m going to talk a bit today about preventative measures, the roles of genetics in clinic and research and gene therapy.
Dementia is really a disease of aging. So there are rare cases of dementia that afflict folks in their 20s, 30s and 40s that are caused by single gene mutation. But, but as we age, our risk of dementia goes up. And folks over 90 years old, 40% of them have dementia. I want a level set on the definition of dementia as an irreversible, progressive loss of cognitive function due to neurodegeneration.
So due to death of brain cells, there is currently no credible evidence that we can reverse Alzheimer’s disease. But the state in 2025 for folks who are cognitively normal is prevention. There’s a lot of risk factors on this slide, that we’ve heard about during the course of the two days here. But if I could highlight two that, I think if you had to put your money on, you should put your money on, it would be exercise.
You already know the benefits of exercise and tight blood pressure control. There is good data from clinical trials that reducing your blood pressure. And I’m in tight less than 120 over 80. That second number diastolic number is likely to drop in the future, especially for folks over 65. This is what you can do to reduce your risk of dementia.
I’m going to tell you a little bit about genetics. We are focused on genetics because I think this is where major medical breakthroughs are coming, is in the genetics space. And I’m going to make a case for why you should care about, rare diseases and rare forms of dementia. So there are rare causes of dementia. I mentioned that earlier in the picture.
Here is Lindy Jacobs in the center with her mother, Allison, who suffers from, a rare form of mutation T so one letter change in the 300 billion letters of your genome is the difference between health and disease, life and death. This family has dementia running in their family. Her grandmother died of dementia. She watched her mother die of dementia.
She herself is a gene carrier. There’s a beautiful article by Virginia Hughes in the New York Times. If you want to learn more about this subject that was published on Christmas Day last year. So there are rare forms of dementia that tell us a lot about the causes of dementia. This is nature’s experiment nature. Nature’s done this experiment.
These are inroads into pure cases of dementia and the path to treating it there. There’s also genetics that are common that affect many of us. A quarter of a quarter of the world’s population carries at least one copy of the APOE4, which increases your risk of dementia. Two copies of that gene increase your risk by 8 to 10 fold, which means 60% of people by 85 that are APOE4 carriers will get dementia.
This is the vision for the gene therapy. So folks will come to clinic. They will get gene sequence. We heard earlier. And I agree with this probably by birth most people will be sequenced in the future. From that sequencing we’ll identify causative mutations depicted in red. But we will also get information about their surrounding single nucleotide polymorphisms.
These are normal differences between your two gene copies. So the copy you got from mom and the copy you got from dad. And we can target those using CRISPR, which is a technology that allows us to selectively target the genome for changes. We in my lab use that technology to cut out those mutations from the genome. And then the cell repairs that DNA cut, removing the mutation from the genome.
We selectively target mutations or the allele so that we can observe as much of the normal gene function as possible. We recognize that we don’t know everything about every genes function in the in the body, and that genes are doing good things that promote health. And so I want to give you an an overview of where we are currently, on CRISPR discovery and optimization for our lead target seen in C9orf72, which is a leading genetic cause of both FTD and ALS, and we’ve essentially cured that disease.
In addition, patient stem cells and stem cell drive neurons we’re testing. And in mice currently we have other indications for genetic causes of FTD, Alzheimer’s disease and genes we’re targeting in Parkinson’s disease. So the CRISPR part in a dish is essentially done. But we do not yet have a therapy for humans. And why is that? Because the CRISPR gene targeting is only one half of the therapy.
The other half is delivery. We have to be able to get this technology into patients brains and spinal cords, and that is the major roadblock in the entire world right now. So, this challenge of delivery for CNS, therapeutics is compounded by, I think the way that we currently road drug discovery programs, the current model of the traditional model of drug discovery was really built for small molecule molecules, and it is failing in the current age of humanized biologic therapies.
I think our drug discovery pipeline is essentially built to find failures, and I know that is controversial to say, but I say that because it mostly finds failures. So clinical trials mostly find things that don’t work in humans. Why is it. So the traditional pipeline you need to look at the specifics is that you test a whole bunch of things in cells or mice in your lab.
You find a few things that you carry on to further animal testing and enabling studies. And the first time that that therapy is ever tried in a human has clinical trial where patients are hoping for a benefit, and where we often find that the therapies don’t work. If the clinical trial pipeline and the drug discovery pipeline is mostly finding failures and human, brain delivery is an exceptional challenge, then what is the path forward?
We know from animal studies that particularly for CNS delivery, the animal studies do not predict what works in humans. So we know this from the AV literature. We know this from other delivery modalities. The human brain is bigger than animal brains. But it’s not just a bigger brain. I drew the human brain, non-human primate brain or rat brain to scale.
I couldn’t put a mouse brain on this slide because it’s too small. But the species specificity problem is a real problem for human therapeutics, particularly the amazing humanized work that many folks are doing now. We want to revolutionize this platform of drug discovery with the most rational, logical next step, which is that we need to do discovery research in human tissue.
How can you do that safely? We have built a platform at UCSF in collaboration with Neil Single, who is a critical care physician scientist, to use brain dead subjects to do some scary research. So these are folks who are dead from by neurologic criteria. They’re usually in the ICU. So they still have blood perfusion. But they are clinically dead.
This is the typical source of organ donation. But there are folks who can’t be organ donors. And there’s families who want to make meaning out of that death. They can participate. Those family members can consent for their, deceased loved ones to participate in our study. And we can test hundreds to thousands of CNS targeted particles in a single brain dead cadaver across all modalities.
HIV is lipid nanoparticles, viral particles, peptides. And we’ve opened this, but we haven’t done this platform yet as we’ve just spent a few years building it. We’ve opened it up to the best particle makers in the country, and we are ready to solve the CNS delivery challenge. What that looks like in a dish. These barcodes are genetic barcodes, but we also put functional tags on them.
We put an mRNA in these barcodes that the cell has to translate into a protein that turns the cell green. So we can see where all those particles went. And then we can use sequencing to identify the composition of that particle and what route of administration it used to get to the to the organs and cell types of interest.
The new pipeline would look something like this. We would test first in human tissue. We would find candidates that we already know will work in humans. Right at the outside of testing. We take those lead candidates back to animal models for toxicity testing. And by the time that that that candidate gets to clinical trials, we have hopefully decreased the time it takes to do discovery research, to human translation and increase the effectiveness of clinical trials, which would ultimately reduce reduce the cost of clinical trials.
We are hoping to develop first and class genome therapies for neurodegenerative diseases. We’re starting with the leading genetic cause of FTD and ALS. But we want to rapidly translate that to more to genetic cases that affect millions of folks around the country. We use novel strategies to remove the mutations, while preserving as much of the normal gene function as we can.
And really, the innovation is screening and human platforms. I didn’t have time to talk about the bioinformatics and biomarker discovery that goes along with this work, so that way it can be ready for clinical trials, and hopefully be a roadmap, to cure other monogenic diseases over time. Thank you.