CSO Corner Volume 8: The Importance of Models

Hello fellow members of our KS family!

For this newsletter, I’d like to talk about the importance of models in studying rare diseases like Kleefstra Syndrome (KS), and why we’ve invested in creating cell line models which are now being released to the research community.

In order to treat a condition like KS, you first have to understand it, and at a very deep biochemical level. To build this understanding, you need to be able run experiments that reveal the underlying cellular disease mechanisms. One way to do this is to develop model systems that you allow you to easily test hypotheses in the laboratory. This also provides a safe and relatively economical way to investigate potential treatment leads, using the developed models.

Although KS is a condition that affects the whole of the individual, it is primarily a neurodevelopmental disorder (NDD). Therefore, I’ll focus this discussion around modeling the neurological state of someone with KS. The central nervous system is an exquisitely complex assembly of neurons and many of other types of cells, all interacting to control how we perceive and react to our environment. How could we possibly hope to understand something so intricate, as well as how this system has been altered in a KS patient?

That challenge remains substantial, but induced pluripotent stem cell (iPSC) technology has vastly improved these types of experiments, for over a decade. In this technology, skin or blood cells are collected from a donor, and then coaxed into becoming stem cells, which are capable of becoming any tissue in the body. With additional coaxing, they can become neurons (or other types of cells in the brain).

Remarkably, when you create neurons from iPSCs and grow them in a dish, they will connect with each other and begin firing, much as neurons do within brains. And it has been shown in KS that neurons grown from patients will display a distinct phenotype. This makes it possible to connect the genotype of the patient (the genetic change) and the phenotype of the patient (the clinical condition) together in a model system that can be extensively studied. It opens the door to understanding mechanisms at a very deep level, and then testing potential treatments to see if they compensate for (or even correct) those mechanisms.

So why did we choose to create our own iPSC lines? Can’t researchers just make their own if they want them? There are three major problems we help solve for researchers by creating these lines and making them available:

• Patient access: To make lines from a KS patient, you obviously need a patient. You’d be surprised how many researchers are interested in studying disorders like KS but (due to it being a rare disease) don’t know any patients. This is part of our important role, and frankly, part of our power, as a community: we are the patients and families!
• Cost: Making cell lines is expensive. If a researcher has to make lines before they can even do their initial experiments, the barrier to entry can be too high, so they may not ever start in the first place.
• Timeliness and ease of access: Many lines can get caught up in paperwork and intellectual property considerations when they are requested for transfer between institutions, making it slow and difficult to get them transferred. Again, this is a barrier that can slow researchers down, or keep them from starting work in the first place. We can provide lines promptly to those who need them, with a very simple process.

I am delighted to report that four research groups have already requested access to these cell lines, and we are in the process of transferring them out so that new experiments can be done to better understand KS, and find possible treatment leads. We can’t wait to see what new science comes out of these lines!

I want to close by thanking the anonymous donors that provided the samples used to create these lines. They were selected in a rigorous process that focused on finding an ideal KS patient to use for a model cell line, based on genotypic and phenotypic considerations. When we asked, they were immediately all-in to help us with this project.

And of course, I should also thank the many donors to IDefine: You helped fund the creation of these lines. Thank you!

Until next time,

Eric Scheeff, PhD

IDefine Chief Scientific Officer