Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Xinyu Zhao, Professor, Waisman Center and Department of Neuroscience, University of Wisconsin-Madison

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Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will accelerate development of breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.”

Hello and thank you for joining us, Professor Zhao! Before we begin the interview, could you please introduce yourself to our audience?

Xinyu: Hi, my name is Xinyu Zhao, I’m a professor of neuroscience. I’m also an investigator at the Waisman Center at the University of Wisconsin-Madison. This is a public university funded by NIH and private foundation and also the State of Wisconsin.

What has inspired or led you to research on Fragile X? What issues are you trying to address?

Xinyu: So I started working on Fragile X when I was a new assistant professor starting my lab in New Mexico. During my post-doc training, I was working on neural stem cells and plasticity and regeneration. And because of my interest in regeneration, I was working on adult neurogenesis. Adult neurogenesis is important for learning and memory and in lifelong learning memory. And so when I ran into this question about the Fragile X syndrome, I become really interested in knowing how the lifelong learning deficit… Basically, I became interested in answering the question, whether the lifelong learning memory deficit might be rooted from defect neurogenesis. And also at the time I had three little children myself, and so I became really interested in knowing the basis of a genetic neurodevelopmental disorders and try to find a way to treat that, from the point of view of a parent. And so that’s how I started working on Fragile X syndrome.

So the first question I tried to answer using the mouse model was whether neurogenesis is defective in the Fragile X mice, and indeed we found that. Using that model, we identified the number of molecular targets and potential drug targets that might be feasible for developing therapies for Fragile X syndrome. And more recently I became interested in extending the mouse study into human studies. The reason is that many of the research based on mouse models have not really translated successfully into clinical trial and the treatment. Since I moved to Wisconsin 11 years ago, I’ve been working on human stem cell models derived from Fragile X patients. And that’s our more recent discoveries and research.

What approaches are you taking in regard to gene therapies, targeted therapies, drug repurposing, or others?

Xinyu: We kind of have a two-pronged approach. In my lab, we actually use parallel mouse models and the human patient-derived iPS cells. The reason we use these two models is because, in the mouse model we have, we could test some of the potential drug targets and for the purpose of drug repurposing. And we can use behavior outcome as a readout for some of this drug effect. Because of the limitation of the mouse model, we also use the human iPSC, induced pluripotent stem cell, models. Using those models, we try to understand the molecular mechanism underlying the function of a Fragile X gene, FMR1. From that, we can identify novel pathways and the novel altered mechanisms, providing the knowledge basis for drug development.

What is the greatest and differentiated value of your modality or technical approach towards the treatment of Fragile X patients?

Xinyu: One of the most important works we are doing recently is to derive iPSCs from patients with a distinct behavior and brain electric activity phenotypes. The reason we want to do that is because there’s a really diverse kind of representation and severity among Fragile X patients, and this diversity has contributed to a lot of the complexity in clinical trial design and the readout.

So because of that, we decided to derive the iPSC stem cells from the patient with a distinct representation in their severity and drug response. And this is a collaboration with clinicians, basic scientists and computation scientists. Our goal is to try to identify, what are the underlying mechanism for these differences in severity, and can we develop an in vitro model in the cell culture model that we can test some of these drugs before they need to be applied to human clinical trial or patient treatment? So this is really exciting, because this is highly relevant to what actually need to be applied to patient in future and highly relevant to some of the more pressing and fundamental questions in Fragile X research and treatment.

Could you tell us your research progress so far? What is the next milestone?

Xinyu: Using mouse models we actually made a lot of interesting discoveries. We published quite a few papers and some of those mouse studies are now being tested in human stem cell models. We also collaborated with other people testing some of their discoveries in our human stem cell models. In terms of the human stem cells, we derive them into neurons in culture. And though we measure their electric activity, their molecular changes, we have actually discovered some very preliminary data showing differences among different Fragile X patient-derived neurons. And we are not sure even these are the underlying molecular differences among patient diversity, but this is the first step. So we’re really excited about this discovery. As for the next step, this work is right now ongoing, and we hope to have publications in the next couple years and to really contribute to the knowledge of Fragile X field.

How do you think we can better address the complexity of Fragile X disease biology in order to identify new targets and biomarkers?

Xinyu: So, Fragile X syndrome is, wow, a really complex disorder, even though there is, in most cases, a single gene mutation. The outcome and the representation of the symptom severity is quite different. Based on what I see, I would say that the kind of approach that may actually help us to develop better understanding and treatment is to use multiple different models. I talked about the mouse models and human stem cell models in my lab, but I also know people are using rat models and other type of models. I think in the future, if possible, we really should try to include more than one type of model, because each of the experiment model has its strength. If we can actually achieve our knowledge from using different models, we’ll be able to achieve our goal much easier.

In addition to that, I really do think that we need to study the relevant cells from the patients, actually iPS cells, because we can differentiate them into neurons. Of course, if we have access to neurons directly, it will always be the best model, but that’s not possible. So when we derived iPS cells from blood, or skin fibroblasts, we can differentiate them into different neuronal types. And that give us models to study how and what kind of molecular pathways have gone wrong in different Fragile X patients. And then we can also identify convergent molecular changes and drug targets that may be in subpopulation patients, because it is possible that the diverse phenotype and representation of severity is rooted from a molecular mechanism that’s somewhat different in different patients.

In your view, what would you recommend the Fragile X researchers to do differently in order to advance better medicine faster for the patients, and what do you hope to see in the Fragile X R&D in the next 10 years?

Xinyu: I know there are a lot of talking about reactivating or reintroducing the gene into patients as a therapy, and I feel that before we know the function of the gene and what kind of off-target effect it can have when you overexpress it, we really need to know more about how this gene can be reactivated or reintroduced and the impact of misexpression. In addition to the current models, large animal models will be really useful. And so far other than mostly mouse models, rat models and human stem cell models, there’re really not that many large animal models for studying Fragile X syndrome. I think, even for gene delivery and drug delivery, large animal models will be really useful.

And the other thing is, the Fragile X patient-derived iPS cells are actually very useful for us to understand the mechanism underlying the different symptoms, different phenotypical diversity among patients, and for us to test the drugs, because not all the patients respond to the same drug the same way. If we can have the iPSC models, we can address this issue and that will give us knowledge of which path we could target for which set of patients. So we have started on that with our work, which was initially funded by FRAXA and also by John Merck Fund. Now, we are expanding that work to study and unveil the mechanism underlying these differences. I think more of this type of work should be carried out.

Are there any innovative collaboration and partnership models that the Fragile X community can pursue to advance the field faster?

Xinyu: Definitely. Without that pilot funding from FRAXA and also from John Merck Fund, we would never have been able to derive these iPS cells from this group of patients. I’m referring specifically to our collaboration with Dr. Craig Erickson at Cincinnati. He has patients from this group and also extensive clinical information of these patients. So the partnership with John Merck Fund and with FRAXA have made a huge difference in terms of progress in this area.

Now we have the system, there are pharmaceutical or biotech companies getting interested in working with us to test some of their drugs, because we have a good readout for neuronal excitability and mitochondria deficit or the different kinds of molecular changes we have detected in Fragile X neurons. So I think this type of a partnership and the pilot grant from non-federal funding will be very important to initiate this type of exploratory projects.

And in the future, I think it’ll be really nice to have collaborative funding from multiple modalities, including federal and private foundation and pharmaceutical companies, and putting the money with academia to investigate specific questions together, because each part have their own goal, but together we can actually form this unified goal to try to answer this really important question and help the patients and the treatment development.

Patient-centric drug development is very important in achieving high quality healthcare. What does it mean for you in the Fragile X field?

Xinyu: Of course our primary goal is to help the patients eventually. I’m a basic scientist, so my first question is always, what is the mechanism behind this? Then once you discover the mechanism, you want to know, can we use this mechanism to help the patient in the long run? I don’t run clinical trials, but when I think about the long term goal, that actually motivates me to work really hard in my research projects. However, we realize that when we are doing basic research, we need to think about patients, and not just your knockout gene or inactive gene, then you have this consistent changes in every single individual, since we are very diverse in our genetic background and in our environmental exposure.
So to develop that kind of patient-centric drug development, we actually have to treat the patients. We really need to think about that; they are not uniform. There are subgroups and there are differences in us. There’s severity and there are phenotypic presentation, and we need to consider that from the basic development of a molecular mechanism and identifying drug target all the way to clinical trial. If we don’t do that, we may end up with a very complex outcome that we cannot interpret. So, what I’m saying is that, we really need to develop this kind of patient-originated cells and the models.

One reason why the Alzheimer field is advancing so fast is because they have a lot of postmortem brain tissue. Whatever they discovered in animal model, they can go into the human brain tissue to check if those changes really are there. But in the Fragile X field, we have very limited access to postmortem brain tissues, so those patient-derived iPS cells are good, but they’re cultured cells. They’re not from those patients who have suffered from those condition. So it would be really good to have an expansion of the brain bank. I know this is very challenging. We have worked with the Maryland brain bank trying to get some of the tissues and it’s really, really difficult. There’re very limited number of tissues available. So if we want to make a really big push for advancement of this field, we need to think about all the challenges. We obtain a lot of information from animal models, and one of the most challenging part in our work is to check that information in human neurons and human postmortem brain tissues.

If we think beyond Fragile X for a moment, in 2021 the FDA approved 50 new drugs. Now let’s imagine 2030, do you think we would collectively be able to achieve 100+ new drug approvals at half of today’s costs? And if so, would there be any major gaps to bridge or any upcoming breakthroughs that you are most excited about?

Xinyu: So I think drug discovery will actually become cheaper, in the sense that for many of the studies, we can use patient-derived iPS cells as a model to test before actually testing in human. So the advancement of human genetics and single cell analysis in recent years has unveiled many molecular pathways and many cell types that either share between humans and animal models, and also identify molecular pathways that can be unique to humans. Some of those pathways are important for drug targets. In the past, we have depended on animal models or cultures, like for example, white blood cells, as a model to testing our theories and our experimental hypothesis. And the limitation is animal models do not always represent the genetic background, the genetic changes in humans, and blood cells are not neurons.

So the patient-derived iPS cells and human neurons really provide this unique opportunity for us to test a lot of our hypothesis. And also the single cell genetics and the extensive fast advancement of human genetics can actually identify all those changes we didn’t even realize. With the gene network analysis indicating what pathways might be changed in a disease versus a control healthy group, in cell type specific manner, this is really powerful development.

I know many people already take advantage of this advancement and they develop novel software and methods to identify drug targets and potential ways to manipulate the disease conditions, so we can achieve a treatment. It would be really exciting to work in this field in the next few years to see how this develops. We are also working with computation scientists and bioinformaticians to use sophisticated computation method, including machine learning, to identify the changes at the different type of neurons in the brain, in the context of not just Fragile X, but also other diseases. So, I think this is really exciting time for drug development.

Thank you so much for your inspirational insights, Professor Zhao!

Xinyu: Thank you.



Xinyu Zhao


Dr. Xinyu Zhao graduated from Peking (Beijing) University with a B.S. degree in Biology and then earned her Ph.D. degree in Pharmacology from the University of Washington (Seattle). She obtained postdoctoral training on neural stem cells from Dr. Fred Gage at the Salk Institute for Biological Studies (La Jolla, California). Dr. Zhao started her own independent research at the University of New Mexico School of Medicine in 2003 and then moved to the University of Wisconsin-Madison in 2011. She is currently a Jenni and Kyle Professor in the Department of Neuroscience and an investigator of the Waisman Center. Dr. Zhao’s research focuses on understanding the molecular mechanisms that regulate brain development with the goal of developing novel treatment strategies for neurodevelopmental disorders including fragile X syndrome. She was recognized with a Research Award from the National Fragile X Foundation in 2018.

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