VGAM is the First Cause of Congenital Cerebral Vascular Malformation in Children
Cerebral vascular malformations can be defined as defects in blood vessels formation in the brain. Up to this day, five main types of malformations have been identified. The project supported by the foundation focuses on a rare congenital defect of cerebral vascularisation called the aneurysmal malformation of the vein of Galen (VGAM).
This malformation is due to the abnormal connection of certain arteries to a large vein called the Galien Vein. By bypassing the capillary network of small cerebral vessel, these arteries induce an increase in cerebral blood flow and consequently an overload of brain vessels responsible for severe complications: heart failure, liquid accumulation in the brain (hydrocephalus) and cerebral haemorrhage.
VGAM encompasses 30% of cerebral vascular malformation in children. Despite significant therapeutic progress it is still associated with a high risk of deadly complications.
This malformation is also frequently associated with other health issues such as an abnormal increase in skull’s volume (macrocephaly), visible vessels on the face and scalp, as well as cardiac and cutaneous vessel abnormalities.
Even though treatments such as endovascular surgery have improved patients’ care, they are still associated with a high risk of complications and mortality rate. Mutation in genes known for their role in blood vessel formation and brain cell connexions have been identified in patients suffering from VGAM and other congenital vascular malformations. These mutations can be inherited or spontaneously appear in children, suggesting a link between brain and blood vessel development that would be altered in patients with VGAM.
This ambitious project, supported by the Plowiecki Foundation, is led by Alessandra Pierani, Nadia Bahi-Buisson and Camille Maillard at Institut Imagine. It explores the link between genetics, vascular and cerebral development in VGAM.
A New Perspective for Studying VGAM: Examining Neuro-Vascular Interactions
The laboratory «Genetics and development of the cerebral Cortex” led by Alessandra Pierani at Institut Imagine has discovered that persistence of transient neural cell in adults is associated with neurological disorders such as temporal lobe epilepsy.
Previous work of this research team suggests that transient cells interact with the vascular network during development and affect cerebral blood vessel formation. Moreover, the researchers observed that deprivation of these cells in mutant disrupts the development of blood vessels in the brain. These elements support the hypothesis that the normal development of neurons is intertwined with the one of brain blood vessels.
The research team aims to uncover how vascular expansion influences neuronal formation, and conversely, how neurons modulate vascular growth. The team intents to determine how the reactivation of developmental process could play a role in the onset of neurovascular disease such as VGAM.
Methodology and Research Aim
Aim N°1: Understanding How Genetics Affect the Clinical Severity of VGAM
The researchers hypothesised that certain genetics variations related to blood vessel formation could disrupt the communication between nervous and blood cells during development. Consequently, brain development and especially the cerebral cortex could be affected. This could be due to direct mutation affecting cortex precursor cells or by indirect environmental vascular abnormalities.
Another hypothesis that the scientists would like to investigate is that a two-septs genetic mechanism could explain the heterogeneity of symptoms in VGAM. This means that a first set of genetic mutations would be inherited from parents but that the manifestation of symptoms would require a second mutation that would occur after fecundation in some foetal cells.
To address these questions, the researchers will analyse a cohort of foetal cases from the prenatal diagnosis center at Necker-Enfants malades hospital. They will identify the link between genetic abnormalities and clinical manifestation of VGAM.
Aim N°2: Understanding the Interplay Between Vascular, Neural and Other Cerebral Abnormalities Within the Brain of VGAM Patients
The second aim of this project is to explore the links between brain blood vessels abnormalities and other cerebral malformations. To do so, the team will use different models such as human cells and murine models. These combined approaches will help to understand the shared mechanisms of these anomalies and to identify all the genes involved.
This study will focus on three genes which play a key role in the development of neurons and blood vessels. Researchers hypothesized that the mutation in these genes could interfere with the formation of transient neurons which are significant for establishing vascular and cerebral connexions.
To study these interactions, the scientists will test if the presence of transient neurones impact the development of normal blood vessels and reciprocally. Thanks to cutting edge microscopy techniques, they will analyse at the cellular level the interaction between transient neurons, cells from blood vessels and cortical progenitor cells.
Simultaneously, they will use in vitro models of human neural cells mutated for the genes of interests. These cells will be derived from induced pluripotent stem cells (IPSC). IPSC are cell lines obtained from adult cells that were reprogrammed to regain their ability to differentiate into several cell types. The researchers will generate neurones and neural progenitor cells from these IPSC that will be directly derived from patients or genetically modified by CRISPR CAS9 (a genome editing technique) to mimic the mutation observed in patients. Thanks to these cells, they will be able to study how the mutation of identified genes will affect neuron survival rate, migration and differentiation.
Finally, these results will be completed by studies on genetically modified mice models depleted for transient neurons or carrying mutations for the genes identified in patients.
Thanks to these complementary approaches, the researchers hope to deepen their understanding of the interconnexion between vessel and neuronal development and to propose new therapeutic strategies for managing neurovascular conditions such as VGAM.
Perspectives
The results obtained in this study will open new perspectives for the care of Developmental Vascular Anomalies (DVA) and Arteriovenous Malformations (AVM). They will have practical applications within the Necker-Enfants malades hospital network, in close collaboration with the Multidisciplinary Prenatal Diagnostic Center, the neuroradiology department, the neurosurgery department, the neuropediatric department, as well as all genetics experts at Institut Imagine. International partnerships are also intended with research centers of excellence in the United States.
Project Leaders at Institut Imagine
Alessandra Pierani is a Research Director at the Centre National de la Recherche Scientifique (CNRS). She is leader of the team “Genetics and development of the cerebral Cortex” and has a dual affiliation with Institut Imagine (Hôpital Necker-Enfants malades, Paris) and the Institute of Psychiatry and Neuroscience of Paris (Hôpital Sainte-Anne, Paris) since 2017. Her research focuses on the role of transient neurones in the development, trajectory and physiopathology of the cerebral cortex.
Pr Nadia Bahi-Buisson is a Paediatric Neurologist. She leads the program on rare diseases, including Rett syndrome and cerebral malformations at the Necker-Enfants malades hospital, APHP in Paris. She also leads research projects at Institut Imagine within the team of A. Pierani on the genetics and physiopathology of cerebral malformations.
Dr. Camille Maillard is a Research Engineer at Institut Imagine. She focuses on human cerebral physiopathology. She is an expert in molecular biology and cell culture, particularly on the differentiation of stem cells.
This project is supported by the Plowiecki Foundation, a family foundation born from the intimate conviction that innovative research must be upheld. Driven by this vision, it aspires to become a catalyst for scientific initiatives and a collaborative space uniting physicians, researchers, and families.
