The Aneurysm and AVM Foundation is pleased to announce the recipients of the 2024 Cerebrovascular Research Grant Awards. We selected four researchers whose scientific projects showed the greatest potential to improve our understanding of cerebrovascular diseases.
Research Study: A novel tyrosine kinase inhibitor coated flow diverting stent as a drug delivery system for intracranial aneurysms
Primary Investigator: Malia McAvoy, MD MS, Resident Physician, University of Washington
Background: Currently, doctors use less invasive techniques to treat brain aneurysms. They do this by reducing blood flow to the weakened area to prevent it from getting larger. This research will develop a new approach to improve aneurysm treatment. The objective is to develop a special device that slows down blood flow and also uses particular drugs to target the main genetic factors that lead to aneurysms. This device, called a stent, will carry medicine on its surface to address the genetic and biological causes of aneurysm in the brain where they occur.
This approach is newly possible because of an innovative coating technique Dr. McAvoy has developed that will allow us to place therapeutic drugs on the surface of stents and have the stent release drugs over a long period of time. With this new device, patients can avoid the negative side effects that often occur with various drug treatments, and at the same time receive treatments that target the root cause of the aneurysm.
In this research project, the first step is to coat stents with drugs and confirm that the drug coating is stable on the stent surface. The second step is to measure how quickly or slowly the drug releases from the surface of the stent. This will be done using 3D-printed models of actual patient aneurysms and simulating blood flow.
Research Objective: The goal of Dr. McAvoy’s proposal is to test if localized TKI drug delivery from the surface of existing endovascular devices currently used to treat IAs could be used to treat fusiform IAs as an innovative treatment solution.
Outcomes: With this grant from the Aneurysm and AVM Foundation, Dr. McAvoy’s hopes this project can help to develop a new treatment approach that will permit personalized and targeted drug delivery for the treatment of brain aneurysms.
Source: Malia McAvoy, MD MS, Resident Physician. This research summary has been adapted and edited from Dr. McAvoy’s research proposal.
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Research Study: Targeting cell adhesion molecules for treating brain arteriovenous malformation
Primary Investigator: Eunsu Park, Assistant Professor, The University of Texas Health Science Center at Houston
Background: Brain arteriovenous malformations (bAVM) often cause intracerebral hemorrhages (ICH), which are associated with a 40-52% rate of mortality and morbidity. Surgical removal of bAVMs is an applicable treatment option; however, this may lead to significant damage to normal brain tissues in the case of deep brain AVMs. Dr. Park’s goal is to develop pharmacological treatment options for inhibiting bAVM-caused ICH.
Clinical studies report that up to 63% of human bAVM patients harbor KRAS mutations in the endothelial cells. KRAS is a family of small guanosine triphosphatases (GTPases) that is a binary molecular switch to turn on/off genes related to cell cycle, differentiation, or survival. The KRAS mutation is detected explicitly in brain vascular ECs. Based on the evidence, Dr. Park has established a novel bAVM mouse model by inducing KRASG12V mutation in brain ECs using brain EC specific AAV capsid. The KRASbAVM mice model recapitulates human bAVM pathology, including tangled vessels, spontaneous ICH, and neurological deficits. However, the mechanisms by which KRAS mutations cause ICH remain unclear.
This leads to their central hypothesis that inhibition of CAMs reduces M/M activation/infiltration, preventing ICH in KRASbAVM mice. This will be tested through long-term & simultaneous inhibition of CAMs to test if the long-term VCAM1 or simultaneous CAM inhibition reduces M/M activation/infiltration and ICH. Dr. Park's team will also determine the fine stereotaxic coordinate of bAVM nidus using MRA and mouse brain atlas by injecting a cocktail of CAM MAbs into the bAVM nidus in KRASbAVM mice, testing the ICH using MRI/A and histology.
Research Objective: The goal of Dr. Park’s proposal is to uncover a causative role of CAMs in M/M activation/migration, causing bAVM rupture/ICH and will provide evidence for a pharmacological strategy for inhibiting bAVM-caused ICH.
Outcomes: Using this grant from the Aneurysm and AVM Foundation, the completion of Dr. Park’s preclinical study hopes to be useful in the development of an inflammation-modulation strategy to stabilize bAVM in patients.
Source: Eunsu Park, Assistant Professor, The University of Texas Health Science Center at Houston. This research summary has been adapted and edited from Dr. Park’s research proposal.
Research Study: A Prospective Study Examining Mobility and Sleep after Aneurysmal Subarachnoid Hemorrhage using a Wearable Fitness Tracker
Primary Investigator: Matthew K. McIntyre, MD, Neurosurgery Resident, Oregon Health and Science University, Portland, OR
Background: Aneurysmal subarachnoid hemorrhage (aSAH) carries high long-term morbidity. The vast majority of aSAH research focuses on the inpatient management of this disease with the frequent classification of a ‘good outcome’ as a modified Rankin score (mRS) of ≤2. However, even among this group of functionally-independent aSAH patients, nearly two thirds report dissatisfaction and participation restrictions with their daily activities especially with housekeeping, chores, and physical exercise at 6 months post ictus. At 1 year, 33% of aSAH patients report ongoing issues with fatigue, cognitive problems, and emotional problems that are associated with poorer mobility and learning.
Sleep dysfunction occurs in up to 37% of aSAH patients often affecting patients beyond one year post-ictus and is associated with poorer quality of life.This dysfunction likely has profound implications on return to work and functional independence. It remains unclear what the burden of poor sleep is on a day-to-day basis for aSAH patients and what the implications of this deficit is on their functional outcomes after discharge. There is a growing body of evidence that high quality/quantity sleep is associated with improved learning, attention, physical activity, and recovery from brain injury, however this knowledge has not yet been leveraged for improving aSAH outcomes.
Wearable technology, including commercially available fitness trackers such as those produced by Garmin, Fitbit, and Apple, offer unprecedented insight into a patient’s functional status. To date, wearable technology has been shown to identify early post-operative complications, increase physical activity, improve health-related cancer outcomes, and, in the spine literature, to improve post-operative mobility. At this time, we have little understanding of the ‘expected’ time to return to normal sleep patterns after SAH and others have gone on to suggest that there may be distinct subgroups of aSAH patients in terms of recovery patterns. Wearable devices will likely play an ever-growing role in the comprehensive evaluation of patient-centered health outcomes. The goal of Dr. McIntyre’s project is to leverage the emerging data behind sleep and mobility science to improve the functional outcomes of their aSAH patients.
Research Objective: The goal of Dr. McIntyre’s proposal is to establish the expected time to sleep and mobility recovery, develop a granular understanding of the influence of in- and out of- hospital interventions on sleep and functional outcomes among aSAH patients, and to compare objective measures of mobility and sleep via a fitness watch with patient reported outcomes.
Outcomes: With this grant from the Aneurysm and AVM Foundation, Dr. McIntyre hopes his research can help patients set realistic goals and to identify patients who are failing to meet these goals in order to allocate specific interventions such as sleep coaching and/or intensive physical therapy programs in order to improve their functional outcome after aSAH.
Source: Matthew K. McIntyre, MD, Neurosurgery Resident. This research summary has been adapted and edited from Dr. McIntyre’s research proposal.
Research Study: Role of IL-17 in Neurovascular Dysfunction after Subarachnoid Hemorrhage
Primary Investigator: Ananth K. Vellimana, Assistant Professor, Department of Neurological Surgery, Washington University in St. Louis
Background: Rupture of a brain aneurysm primarily leads to bleeding at the base of the brain and results in a condition called subarachnoid hemorrhage (SAH). Patients who experience SAH have a devastating outcome with around 45% death within 30 days after the bleed and significant disability in nearly 50% of survivors. Two forms of secondary brain injury which are initiated by the aneurysm bleed, called Early Brain Injury (EBI) and Delayed Cerebral Ischemia (DCI) account for the majority of poor outcomes after SAH. While EBI occurs in the first few days after SAH, DCI typically occurs between 4-10 days after the initial bleed.
Recent studies have identified a variety of factors that lead to the development of EBI and DCI after SAH. Among these factors, inflammation in the blood, cerebrospinal fluid, and brain tissue plays a key role. A cytokine called IL-17 secreted by various cells of the immune system is a key contributor to the post SAH inflammatory response and has deleterious effects.
In this study, Dr. Vellimana will utilize a well-established mouse experimental model of SAH to understand whether inhibition of IL-17 using medications and genetically (via mice that lack IL-17) provides protection against EBI and DCI. If successful, additional studies will be performed in other animal models of SAH, with the ultimate goal of translating IL-17 directed treatment to patients with SAH.
Research Objective: The goal of Dr. Vellimana’s proposal is to test the hypothesis that increased IL-17 production after SAH contributes to the development of EBI, DCI and long-term neurobehavioral dysfunction.
Outcomes: Using this grant from the Aneurysm and AVM Foundation, Dr. Vellimana hopes the research will be able to translate from experimental models to patients, as several IL-17 inhibitors are already FDA approved for conditions such as psoriatic arthritis and ankylosing spondylitis.
Source: Ananth K. Vellimana, Assistant Professor, Department of Neurological Surgery. This research summary has been adapted and edited from Dr. Vellimana’s research proposal.
