Tackling Juvenile Batten Disease with Gene Editing in Complex 3D Cellular Models


We had the pleasure of speaking with Dr. Gemma Gomez-Giro, a CONNECT researcher from Luxembourg, whose research involved the development of an in vitro cellular model for juvenile neuronal ceroid lipofuscinosis (JNCL), more commonly known as Batten Disease, using genome editing techniques in hiPSCs to help recapitulate and understand the biological mechanism in a 3D organoid system.

Additional value of in vitro human organoid cellular disease models to animal studies and drug discovery models

PERKINELMER: What do you think is the current state of in vitro 3D complex models in disease modeling and related drug discovery efforts? Do you anticipate further adoption and implementation in the future for basic research and other applications?

DR. GOMEZ-GIRO: I believe this [continued adoption] is already happening. The 3D organoid technology has been developing for quite some years now and there are in vitro 3D complex models for different organs that have been used to study diseases in different systems.

When we compare to traditional 2D in vitro cultures, we believe that by increasing the level of culture complexity we will be able to study diseases at a more physiological level. So, I can only expect that the field will keep evolving in this direction.

PERKINELMER: In your opinion, what extra value would in vitro human cell models add in accelerating disease research compared to existing animal models?

DR. GOMEZ-GIRO: Animal models are and have been widely used to understand diseases and their underlying mechanisms. They are also very important when it comes to drug testing. However, their main drawback is that sometimes they do not fully recapitulate the features or the effects that the disease has in humans. In other words, the results that are seen in the animal models do not always translate to the human.

Moreover, animal models are also expensive and harder to maintain, and their use raises ethical concerns. In vitro human cellular models allow us to study the disease in specific cell types and in a 3D environment, if we talk about organoids, which brings us closer to the physiological situation in the patients.

hiPSC and gene-editing as tools for the development of organoid models in disease research

PERKINELMER: In your opinion, what are the benefits of developing a model using iPSCs from healthy patient and introducing a targeted mutation instead of using an affected patient-derived model harboring the mutation?

DR. GOMEZ-GIRO: Patient-derived models, such as skin cells obtained from the patients, have the advantage that they are of easy sampling. However, skin cells would not represent the population of interest when we want to study neurodegenerative diseases such as NCL.

These primary human cells can be reprogrammed into induced pluripotent stem cells, or iPSC, which allow us to then differentiate them into the cell type we want to study, like neurons, for example. These iPSC that are patient-derived carry the same genetic background of the patient.

As such, having iPSC from healthy individuals where the disease [mutation has been introduced ex vivo] have the advantage that we can study the effect of a particular mutation independently of the genetic background of the patient. Having iPSC from healthy individuals where we introduced the mutation was also very important in the context of NCL and rare diseases, in which the disease affects such a small percentage of the population that getting patient material to study the disease is very complicated, especially taking into account that the disease affects young children.

Collaboration at CONNECT – Connecting neural networks: Nervous-system-on-Chip Technology – to foster breakthroughs in on-chip 3D organoid technologies of the neuronal systems

PERKINELMER: Can you speak a little on CONNECT and how it’s helping neuroscientists like yourselves with accelerating their research/applications on complex 3D on-chip technologies?

DR. GOMEZ-GIRO: I believe that, in CONNECT, we are going even one step farther when it comes to advancement of 3D complex models, by trying to develop a platform, a chip, that can contain different systems, in this case, different parts of the nervous system.

With a system like that, we can study the interaction and the connection of the different components of the nervous system in vitro, which is crucial, because complex disease such as Parkinson’s disease, can have multiple systems affected; and, it can allow us to study disease spreading from one system to another, for example.

PERKINELMER: What are your thoughts on the importance of collaboration between academia, biotech, and pharma to help accelerate disease research and therapeutics for rare diseases such as CLN3?

DR. GOMEZ-GIRO: I think collaborations are vital, and they are a unique way to bring research forward and to speed up drug discovery and development.

This is crucial in the case of rare diseases because not many labs do research on these topics, and perhaps they may not be perceived as appealing to pharma companies because a therapy would target just a few. Therefore, I believe that the close interaction between the medical doctors – who see the patients – , the researchers – who study the disease –, biotech companies – who facilitate and complement these studies –, and pharma companies – who perform research, development, and test these therapies –, is the only way to more quickly find a cure which is very much needed for these children.

I think this principle is equally important and applicable to any disease, especially those with aggressive progression, regardless of the amount of people affected by the ailment.

About the Scientist

Dr. Gemma Gomez-Giro obtained her Bachelor and Master in Biomedicine in Barcelona, Spain. After a short research stay in Munich, Germany studying Alzheimer's disease, she worked in Prof. Schöler´s lab (Münster, Germany) and Prof. Schwamborn’s lab (Luxembourg) to complete her PhD studies, focusing on the development of cellular models for NCL, a neurodegenerative disease affecting children, via genome editing of iPSCs to introduce disease-causing mutations in the CLN3 gene.

With these cell lines, she derived brain organoids to study the disease in the brain in vitro. Currently, she is a post-doctoral researcher at CONNECT applying the 3D organoid technology that was developed in the lab to study Parkinson's disease with on-chip approaches.