The Aneurysm and AVM Foundation is pleased to announce the recipients of the 2023 Cerebrovascular Research Grant Awards. We selected three researchers whose scientific projects showed the greatest potential to improve our understanding of cerebrovascular diseases.
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Research Study: Elucidating the genetic basis of Vein of Galen malformation
Primary Investigator: Andrew T. Hale, MD, PhD, Neurosurgery Resident, University of Alabama at Birmingham, Department of Neurosurgery
Background: Vein of Galen malformations (VOGMs) are the most common and severe neonatal blood vessel anomaly of the human cerebral vasculature. VOGM are the result of abnormal connections between arteries, veins, and capillary vessels during neonatal development. Even with neurosurgical intervention, VOGM can cause systemic problems such as cardiac failure due to the heart’s inability to accommodate the largest amount of blood flow into the venous system. The VOGM may also cause increased intracranial pressure, leading to brain hemorrhage or impaired draining of cerebrospinal fluid resulting in hydrocephalus. These problems may be life-threatening.
Despite all of this, the cause of VOGM is largely unknown, but is widely hypothesized to be caused by genetic abnormalities. To understand the genetic and molecular basis of VOGM, Dr. Hale proposes the creation of the VOGM Genetics Research Consortium (VOGM-GRC), an international multi-institutional network of the world’s leading pediatric neurosurgeons, endovascular specialists, vascular neurologists, and geneticists/molecular biologists. The team will aggregate genetic data from both germline (i.e., cheek swab DNA) as well as endoluminal biopsy of the VOGM lesion directly.
Understanding the genetic basis of VOGM may broadly inform our understanding of cerebrovascular development and disease pathogenesis; improve clinical prognostication and decision-making; and provide a mechanistic foundation for the rationale use of repurposed drugs and/or design of targeted therapeutics relevant for VOGM and potentially other cerebrovascular lesions.
Research Objective: The goal of Dr. Hale’s proposal is to identify causative genetic and molecular factors governing VOGM development and maintenance, with the goal of repurposing or developing novel pharmacologic therapies to improve VOGM treatment.
Outcomes: With this grant from the Aneurysm and AVM Foundation, Dr. Hale’s team hopes their study can serve as an archetype for applying endoluminal biopsy techniques to pediatric cerebrovascular disease more broadly.
Source: Andrew T. Hale, MD, PhD, Neurosurgery Resident, University of Alabama at Birmingham. This research summary has been adapted and edited from Dr. Hale’s research proposal.
Research Study: Enhancing glymphatic-lymphatic clearance as a novel strategy to treat SAH
Primary Investigator: Humberto Mestre, Resident Physician, Department of Neurology, University of Pennsylvania
Background: Sadly, many aneurysms and arteriovenous malformations (AVM) are diagnosed too late, and they are often discovered after they have ruptured or bled causing a condition known as subarachnoid hemorrhage (SAH). While advances are being made in the earlier diagnosis of these conditions, SAH still remains one of the most common complications of aneurysms and AVM. In SAH, blood traveling in the cerebral blood vessels exits and accumulates around the brain in a space occupied by the cerebrospinal fluid (CSF). Normally, CSF has a composition similar to tears (salty and translucent) and is produced by a specialized tissue in the brain called the choroid plexus. It possesses the perfect combination of water, minerals, and proteins for our brain cells to function properly and this is the fluid typically collected during spinal taps.
One recent discovery suggests that CSF continuously drains into the lymphatic system embedded into one of the linings of the brain called the dura, and this drainage acts as a waste disposal system, clearing out waste that accumulates during the day. After SAH, blood enters the CSF space and wreaks havoc, causing inflammation and adding to the damage caused by the bleed. The breakdown of blood causes blood vessels to clamp down, limiting the amount of blood flowing to the brain. It irritates brain cells causing them to be hyperactive leading to seizures, and it also clogs the drainage routes of CSF causing an abnormal accumulation of fluid known as hydrocephalus.
Current treatments after SAH are primarily focused towards preventing new bleeds and treating the complications, but none are targeted at removing blood from the CSF. But what if we could apply a painless, non-invasive ointment on the neck of patients after SAH to stimulate the removal of blood from the skull? Dr. Mestre’s proposal is based on a naturally occurring compound (prostaglandin F2α) that causes increased lymphatic drainage of CSF and could potentially harness our bodies’ natural abilities to speed up the removal of blood. Their hope is that this treatment could improve recovery and reduce the odds of developing complications after SAH.
Research Objective: The goal of Dr. Mestre’s proposal is to test a novel application of an FDA-approved prostanoid, prostaglandin F2α (PGF2α), in SAH which has been shown to augment transport along cervical lymphatic vessels and enhance CSF drainage in an age-independent manner.
Outcomes: Using this grant from the Aneurysm and AVM Foundation, Dr. Mestre’s team hopes that their treatment strategy could not only improve the recovery of patients after SAH, but that it could also be expanded to treat other diseases such as stroke, traumatic brain injury, or even diseases like Alzheimer’s and Parkinson’s disease.
Source: Humberto Mestre, Resident Physician, Department of Neurology, University of Pennsylvania. This research summary has been adapted and edited from Dr. Mestre’s research proposal.
Research Study: Overcoming barriers in Therapeutics, Imaging and Biomarkers for brain AVMs
Primary Investigator: Gael Genet, Research Assistant Professor, University of Virginia, School of Medicine, Cell Biology Dept
Background: Blood vessels are highly organized networks of arteries, capillaries, and veins. In patients with mutations that disrupt the mechanisms that regulate blood vessel formation – as in the genetic disease Hereditary Hemorrhagic Telangiectasia (HHT) – this can lead to the formation of abnormal, disorganized blood vessels (termed vascular malformations) that are prone to sudden and serious bleeding, particularly in the brain.
HHT affects 1 in 5,000 live births. Because it can vary in its clinical presentation, HHT can be difficult to diagnose. Symptoms often begin in childhood and progress in severity, but patients typically do not receive a definitive HHT diagnosis until >40 years of age. Drugs currently being used to treat that disease are helpful to many individuals but do not work for all patients and cause a lot of side effects. Therefore, it is needed to find new drug treatments to treat people afflicted with this illness.
Dr. Genet’s preliminary results showed that proper control of cell division (or cell cycle) is important for normal vessel formation. Their team found that uncontrolled cell division leads to blood vessel malformations. They will use new mouse models to study the modifications of the cell cycle in blood vessels in normal and disease conditions. They will also test the effects of drugs that are known to control cell cycle to prevent or cure vascular malformations, and develop new imaging techniques to visualize those malformations in the brain.
Research Objective: The goal of Dr. Genet’s proposal is to investigate dysregulation of endothelial cell cycle and identity in bAVMs, and validate the therapeutic potential of cell cycle modulators to treat vascular malformations.
Outcomes: Using this grant from the Aneurysm and AVM Foundation, Dr. Genet’s project will provide new hope for the treatment of HHT patients, whereas current treatments are unsatisfactory and involve invasive surgery or radiation, with considerable risks and undesirable side-effects.
Source: Gael Genet, Research Assistant Professor, University of Virginia, School of Medicine, Cell Biology Dept. This research summary has been adapted and edited from Dr. Genet’s research proposal.
