Elucidating PWS pathophysiology in patient derived 3D human cortical organoids

Funding Summary

In this project Dr. Lodato will use stem cells from PWS patients to generate human 3D cortical organoids (a ‘minibrain in a dish’). Human cortical organoids are valuable models that mimic aspects of human brain development, and analysis of these organoids is expected to shed light on how brain development in PWS differs from that in typical individuals. Dr. Lodato and team have expertise in generating and analyzing cortical organoids, focusing on neuronal function and communication. This work may provide a new understanding of the basis of cognitive challenges in PWS, while offering a valuable platform for scalable drug screenings.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Please find the full webinar for all the funded grants this cycle here.

Lay Abstract

Prader-Willi syndrome is a neurodevelopment disorder characterised by complex spectrum of clinical manifestations, including impaired satiety, severe childhood obesity, sleep abnormalities in addition to intellectual disabilities and social and learning deficits.
Deletion, uniparental dysomy (UPD), or imprinting defects of paternally expressed genes in the human chromosome 15 (15q11-13 locus) are known to cause profound endocrine dysfunctions and abnormal functional connectivity among different brain regions of the PWS patients, including the cerebral cortex and subcortical structures. While the genetic architecture of the disorder has been identified, our understanding of the mechanisms underlying the complex spectrum of clinical phenotypes associated with PWS remains still largely elusive. The PWS locus is evolutionarily conserved and several animal models for PWS have been generated over the past decades, providing instrumental insights in PWS research. One of our team (Tucci laboratory, IIT) has already contributed to dissect the aberrant activity of cortical neuronal networks in PWS mouse model. Although PWS mouse models are instrumental in dissecting PWS phenotypic mechanisms, the emerging species-specific genetic and neurodevelopmental differences motivate us to develop innovative experimental systems to address PWS pathophysiology and explore effective therapies.
In this project we propose to generate human 3D cortical organoids (cOrg), 'miniatures' of the developing human cerebral cortex in a dish, from induced pluripotent stem cells (iPSC) derived from PWS patients (already generated and available for the PWS community). Human cortical organoids are valuable models that better mimic aspects of human cortical development. When derived from people with neurologic conditions, like PWS, these organoids can be used to recapitulate disease processes and are considered of extreme value in accelerating therapeutics. In our laboratory (Lodato laboratory, Humanitas University), we have already optimised a scalable, efficient, and robust protocol to generate 3D cortical organoids as human model of PWS, and compare their molecular and functional features with those of control healthy individuals. Leveraging on the synergistic activity and complementary expertise of the two teams, we will apply advanced technologies and perform a punctual characterisation of these new cellular models for PWS, shedding light on the functional and molecular aspects that are altered in the neurodevelopment of PWS children. We aim indeed at identifying critical alterations in the generation of cortical neurons and their assembly into functional networks, that might cause learning deficits and intellectual disabilities. Our work will provide a new framework to study PWS and lay the foundation to establish an alternative human model system to follow neurodevelopment of patients, while offering a valuable platform for scalable drug screenings.
We trust that this innovative strategy will pave the road for the design of new therapeutic targets which will eventually improve the quality of life of PWS patients and their caregivers.