Reprogramming of somatic cells into organOids: patient-centred neurodevelopmental disease modelling from nascent induced pluripotency

Introduction

Understanding the neurodevelopmental causes and mechanisms of brain disease is challenging due to several factors:

• Limited access to human brain tissues
• The complexity of brain anatomy
• The lack of accurate models to recapitulate human brain development

Advances in Technology

The convergence between induced pluripotent stem cell (iPSC) and organoid technology enables the recapitulation of key features of early human neurodevelopmental disease in vitro. However, there are significant challenges:

1. Low efficiency
2. High cost
3. Technical variability in generating iPSCs and organoids

These challenges make it difficult to design a powered study that associates patient genotype with organoids’ in vitro phenotypes.

Proposed Solution

I will generate technology to produce human brain organoids from selected patients through a robust, timely, and seamless process. This technology aims to capture previously undetected neurodevelopmental phenotypes.

This will be achieved by:

• Combining reprogramming to nascent states of pluripotency
• Facilitating neurodevelopmental morphogenesis in three dimensions

Starting from a single nascent naive hiPSC, we will develop a process to form:

1. An epiblast cyst
2. A neuroepithelial cyst
3. A forebrain organoid in a continuous three-dimensional process

Research Focus

I will use this technology to investigate genetic and epigenetic modifications in the early phase of neural development of Fragile X Syndrome (FXS).

We will generate brain organoids from large cohorts of FXS patients for:

i) Profiling the whole spectrum of in vitro phenotypes associated with the variety of patients’ genetic and epigenetic modifications
ii) Revealing unexplored developmentally regulated mechanisms
iii) Designing a powered study to assess targeted therapeutic options in FXS

Impact

ReprOids will allow the generation of human brain organoids from large cohorts of patients, capturing in vitro the whole spectrum of disease manifestations. This will have a significant impact on patient clinical management at the diagnostic, prognostic, and therapeutic levels.