Modelling the neurodevelopmental phenotype of NF1 using patient-derived stem cells - Health Care Professionals 

It was exciting to see an experimental research study based on a stem cell model included in the program of the recent NF Clinical Symposium in Sydney. The presentation was delivered by Dr Kiymet Bozaoglu, who is a molecular biologist and the project’s team leader in the Neurogenetics Laboratory at the Murdoch Children’s Research Institute in Melbourne.

Dr Bozaoglu is interested in the biological of brain development in patients with NF1. She is an expert in using molecular science to study the genetic basis of the condition and the flow-on effect of a reduced availability of the NF1-protein on the formation of neuronal pathways during embryonic brain development. She hopes to identify where, when and how aberrant mechanisms of brain development cause pathogenic connections in the central nervous system, believed to contribute to neurodevelopmental challenges faced by NF1-patients after birth.

Children with NF1 are known to be at risk of a range of learning and cognitive impairments, but what biological mechanisms at the molecular level drive these anomalous neurodevelopmental outcomes in NF1 remains unclear. So, instead of further improving therapeutic options to manage symptoms of neurodevelopmental challenges during childhood, Dr Bozaoglu concentrates her research efforts on the origin of the problem during the earliest phase of development.

Together with her colleagues, she has successfully developed a stem cell model which represents the first stages of differentiation of pluripotent stem cells into neurons. They are able to stimulate these stem cells to grow into brain specific cortical neurons in a dish, either as a 2D cell layer or a 3D cluster of cells called organoids. The stem cells are generated from a blood sample collected during a visit to the clinic. By using stem cells from individual patients with NF1 as starting material, the model allows analysis of unique characteristics of cortical brain development as a result of the specific NF1-mutant gene variant of each patient.

This patient-derived stem cell model offers a new approach to correlate the genotype of an NF1-patient with the intricacies of disrupted neuronal growth, signalling and connectivity, and its consequences for the formation of functional brain pathways required for learning, cognition and behaviour.

The availability of the developing cells per patient in a dish permits the use of a range of molecular and cellular biology tests otherwise unthinkable. In medical research terms the stem cell model is referred to as a preclinical model with the potential to achieve a deeper understanding of the genetically driven brain processes related to specific mutations in the NF1-gene.

Preliminary data on the growth and analysis of stem cells derived from 6 individuals so far are encouraging, but experimental testing will continue before the model can be scaled up into a platform for in vitro preclinical trials. For now, this research presents a promising new step forward to shed light on what pathogenic features of brain development in NF1 may

impact neurodevelopmental outcomes in later life. But in time, its capability to study patient-specific differences in brain biology may assist personalised therapeutic strategies for NF1-patients with diverse neuropsychological profiles.

You can read more about Dr Kiymet Bozaoglu at the "Get to know Australian NF Researchers" Interview here.

And find the summary of this presentation for Patients and Carers here.