Ahead of our 2022 Virtual KAND Family & Scientific Engagement Conference on August 13, 2022, KIF1A.ORG interviewed core KIF1A Research Network members to discuss their #relentless efforts to understand KIF1A and help KAND patients in this special “Meet the Research Network” series on the KIF1A.ORG blog.

KIF1A.ORG’s Research Engagement Director Dylan Verden, PhD, had the pleasure of talking with Wendy Gold, PhD, associate professor at University of Sydney, and Simran Kaur, research officer at the Murdoch Children’s Research Institute. Drs. Gold and Kaur explain their work to develop drug screens for KAND using mini-brains grown from patient-derived cell lines.


Dr. Gold: Dylan, it’s really nice to be here. I’m Associate Professor Wendy Gold. I’m based in Sydney at the Children’s Hospital at Westmead in the Kids Research Institute, which is a research facility of the hospital. I’m also an academic at the University of Sydney and I have an adjunct appointment at the Children’s Medical Research Institute, which is also based at Sydney. I’ve been working closely with Sim now for ten years and I’m going to hand it over to her to introduce herself.

Dr. Kaur:  Thank you, thanks Dylan, thanks Wendy. Hi everyone, my name is Simran Preet Kaur and you can always call me Sim in short. I’m an early career researcher with professional experience in genetics and molecular biology. I’ve been working in the space of rare disorders for the past 13 years. Currently I’m working as a research officer in Professor John Christodoulou’s lab here in Murdoch Children’s Research Institute, Melbourne, Australia. My journey with KIF1A started as a part of my PhD studies under the supervision of Professor John Christodoulou and Dr. Wendy Gold. Ever since, there is no look back, and we are continuously developing projects, with the support of KIF1A.ORG of course.

Dylan: Broadly, what questions about KIF1A are your projects addressing?

Dr. Kaur: We are working very collaboratively with KIF1A.ORG to identify the questions that still need to be addressed in KAND research to help facilitate the therapeutic pipeline for drug discoveries for KAND individuals. At the moment, we are developing four main projects in the lab. The first project is about high throughput drug screening to find small molecules that help with KIF1A defects. I would like to say with the kind support of KIF1A.ORG, we have been working continuously to develop a pipeline and cellular models which are quite compatible with the high throughput drug screening system. Hopefully we will have certain hits in the coming time that will open up avenues for further drug discovery. The second project that we are quite excited to begin is to find newer treatments for treatment-resistant KIF1A-related epilepsies that our KAND kiddos are going through at the moment. We are quite pleased to let you know that we have been really successful in securing a three-year project grant which is really highly competitive. It is a national grant which is called the NHMRC Ideas Grant. Again, we worked together with KIF1A.ORG to discuss what is the plan we should follow, what are the research questions that are still pending, which really helped us to develop this great project. Several of our KIF1A Research Network members are part of this grant and they will help to study it further. Very briefly, what we’re going to do is: this study will be based on the induced pluripotent stem cells which are derived from our KAND individuals. We will be forcing them to make neurons and brain organoids in a dish that maybe we’ll talk more about later. The idea is to find the seizure phenotype in vitro, in a dish, and compare it with the clinical reports for further designing the high throughput drug screening in order to find the drugs which may be able to help us control the really bad epilepsies in KAND individuals. For the next two projects, Wendy, would you like to share your ideas?

Dr. Gold: Thanks Sim. I just wanted to mention that one of the powerful approaches that we took as far as addressing our current research was to approach KIF1A.ORG and ask them where the gaps in knowledge were. This was one of the first things that Sim and I did. I believe it’s very powerful in connecting with foundations and associations like KIF1A.ORG so we can identify where the gaps are, not overlap with any other researchers, but rather synergize. Sim has been tremendous in doing this by leading this grant. As you mentioned, we have four main streams of research that we’re focused on. The other two are advancing therapies in the gene therapy space. Sim and I are working toward developing a gene therapy that could alleviate some of the symptoms that children with KIF1A variants have. The other area of our research is trying to understand more about the underlying pathophysiology of the disorder so we can identify drug targets, we can identify disease drivers, and move forward with our research. A powerful way in which to do this is “omics” studies. What “omics” studies involve are genomics, transcriptomics, so that’s looking at the message or the gene expression, proteomics, which is looking at the protein expression, and metabolomics, which is looking at the metabolites. In combination and together, if we can intersect all of these pathways, we can find common compounds, common molecules that could be driving the disorder, or could be targeted for therapies. We believe that this holistic approach, these four pillars, are very powerful. We’re very excited about embarking on this journey to find new therapies and also to better understand the disorder.

Dylan: Can you explain why patient-derived stem cells are so crucial, for rare disease research in particular?

Dr. Kaur: So far, whatever studies we’re doing are in the lab, in dish, what we call “in vitro”. Often we need “in vivo” models to validate our findings in the lab. More commonly used models to do these studies are rodent models, such as rats and mice. But still there are quite a lot of differences between humans and mice on the anatomic, embryonic, and metabolic level. Both of them don’t match when we talk about molecular structure and genetic complexity, which is involved in human diseases and especially rare diseases. That’s why we think we need a better model system in which we can validate the findings. iPSCs are a great source. The other thing I’d like to say is usually rare diseases like KAND are brain-related disorders. So it’s not always easy or possible to access a more disease-relevant cellular model such as brain tissues. That’s where the part of iPSCs come in, especially those derived from patient cells. iPSCs can be generated quite simply and quickly these days from samples that can be readily available from affected individuals, such as skin fibroblasts and blood samples. Essentially, they get reprogrammed back to the stage where they’re pluripotent, which means we can push them to make any type of cell within the body, such as neurons and organoids. Thus, we feel that patient-derived iPSCs are quite powerful tools for basic and translational research, especially in the rare disorder field.

Dr. Gold: Sim, that’s exactly right. What we can do is we can take these induced pluripotent stem cells and we can grow them into neurons, which are brain cells, and also organoids, which are called mini brains in a dish. These are both very powerful in vitro models that can be used synergistically with animal models as well to better inform us on underlying pathophysiology and also to test novel therapies. The difference between the neurons and the brain organoids is neurons are still two-dimensional. They lie flat on a dish, a culture dish in a lab, and they can be very informative, however they don’t recapitulate the multidimensional, three-dimensional organizational structure of the human brain. Therefore, we have proposed to use both models: the 2D neuron models for simplicity and efficiency in growing neurons and also the 3D brain organoid model for complexity. In our studies, we’re going to be using both, so that we have both models readily available. What’s exciting about the 3D brain organoid models is that they recapitulate many of the features of the human brain. Some structurally, but most importantly the electrophysiology and the maturity of the neurons, so we can look at really complex molecular and chemical signals in the brain and also how the neurons talk to each other. Especially in the case of KAND individuals, how their seizures arise and how we can prevent the seizures using different drugs to alleviate the symptoms.

Dylan: Do you have any thoughts or messages for the KAND community?

Dr. Kaur: Yes, definitely, thank you so much Dylan. First of all for KAND families, thank you so much for your confidence in us and we really want to let you know that each one of you really motivates us to overcome challenges, big or small, simple or complex, to keep driving this research further. For the lovely KAND kiddos and individuals, your smile is really precious, so keep smiling, and we can’t wait to meet with you in person in the next coming time. And a message for the KIF1A Research Network members is thank you so much for helping us to develop such great programs in the lab. It’s great to be part of such a close-knit network who believe in connection, collaboration, and contribution, and who believe in open science. It’s really exciting and we are looking forward to working with all of you to keep moving this research further.

Dr. Gold: I would just like to add to that to say that the KAND community are actually the driving force behind all our studies. It’s your commitment to finding cures, for finding better treatments, that just cannot be underestimated. The parents and the carers are just so passionate about advocating for their children, raising awareness through social media, through local campaigns. It’s this drive that is actually so contagious that we feed off this, and it’s essential that we keep these relationships because it really drives our research and our passion to find cures and to better understand the disorder.

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