We are making an impact by spreading awareness and helping to fund cutting-edge cavernous malformation and non-cancerous brain tumor research that has the potential to change current diagnostic or treatment paradigms for adult and child patients.  Remarkably, since our founding in July 2015, we have raised over $900,000.

Research Funding provided for our 2022 Micro-Grant Cycle:

Be Brave For Life Research Summary 2022 Douglas McConnell, MD, FACS

The first grant awarded was to an experienced group in Australia that has developed a human tissue model (laboratory only) which mimics CCM. Their plan is to validate this CCM tissue model and then test molecules and polypeptides found in nature for alteration of CCM development. The medical world is filled with drugs and molecules discovered in nature which have contributed to treating and understanding the body. Good examples include digitalis, caffeine, nicotine, aspirin, quinine, penicillin, sulfa drugs, and even the saliva of the river leech. A working human cellular CCM model offers a test bed for many treatment possibilities. (Most of the listed agents above found therapeutic use long before their mechanism of action or chemical structure was understood)

We currently do not know which factors drive CCM lesion growth and incorporation of healthy cells leading to a large, unstable cavernoma. To identify how progression occurs, we will establish a new model system that reflects the mixed nature of progressed CCM lesions. Our team has recently established a three-dimensional (3D) human model of CCM disease. For this project, we will capitalise on this recent advancement. Specifically, our research goals are:
GOAL 1: To improve the accuracy of CCM modelling, by further developing our 3D human model and include
a mixture of mutated and normal cells.
GOAL 2: Perform a drug screen using unique natural compounds libraries (only available at our institute) to
identify new agents that can interfere with CCM disease progression.
GOAL 3: Share our model systems and new drug targets with the CCM research community to further CCM
research more broadly.

— Dr. Anne Lagendijk at the Institute for Molecular Bioscience (University of Queensland).

The second grant is to an experienced group at the University of California in San Francisco. They are looking at identifying a biomarker to perhaps screen and categorize CCM severity. Interestingly, they already have frozen whole blood samples from 50 CCM patients – one half of which had CCM hemorrhage. They will be able to measure what is called DNA methylation which may be a marker to CCM as compared to blood from control patients. “If you don’t look you will never see”.

We hypothesize that DNA methylation profiling may be useful to identify biomarkers for CCM disease severity. We propose to conduct a pilot study to investigate whether DNA methylation profiles are associated with CCM disease severity phenotypes (hemorrhage, total number of lesions or large lesions). This study capitalizes on a large cohort of CCM patients collected at UCSF by Dr. Helen Kim (Collaborator) with detailed clinical and genetic data, and banked specimens, allowing integration with newly generated epigenetic data.

— Dr Shantel Weinsheimer at the Department of Anesthesia and Institute for Human Genetics, UCSF.

The third grant for 2022 has received a previous Be Brave For Life grant. Here they are using a mouse (murine) model which can have induced CCMs. There is evidence that the oncogene (cancer gene) BMI-1 enables rapid growth of new blood vessels in cancer biology. For tumors to enlarge they must stimulate local rapid vascular growth. The hypothesis of this group is that the study of a BMI-1 INHIBITOR chemicals will open a pathway of knowledge and possible treatment for CCM. It is known that vascular stimulating tumor secretions (VEGF) are key to tumor growth. A recent cancer research paper headline links the CCM research to tumor biology:“inhibition of endogenous Bmi-1 in glioma cells markedly reduced glioma cell-induced in vivo angiogenesis. Angio (blood vessel) genesis is a recurring theme that MAY be an emerging link between cancer tumors inducing new blood vessels (Neo vascularization) and the development of CCM. As an aside, ANTI VEGF treatment directly into the human eye has recently revolutionized the treatment of macular degeneration and restores vision! Human Wet Macular degeneration is a vascular proliferation AND then with fluid leaking and a possible hemorrhage component. Sound familiar – like CCM?

Understanding the mechanism through which this drug ameliorates the pathological aspects of CCM disease, will pave the way for the development of a new pharmacological treatment for CCM patients. It will improve patients’ lives, giving them a less invasive therapy and would benefit society, with a dramatic reduction of costs for patients, hospitals and healthcare systems. In addition, as CCM pathological features are shared with different other vascular anomalies, the understanding of the mechanism of action of BMI1i would make me be able to propose it also for the treatment of other vascular diseases.

— Mariaelena Valentino, Open University PhD Student, IFOM ETS, Milan.

The fourth grant is to the University of Chicago Neurological Surgery Department. They also are looking at the link between cancer overgrowth of blood vessels and CCM. They are looking at biomarkers associated with a mutation of PIK3CA. Again this research relies on a mouse model that can be induced for a PIK3CA mutation. These mice tumors may create a microRNA marker in the blood. The grant’s author says it well: “Overall our goal is to transform the diagnosis and treatment of CCM disease using biomarkers, and this study is an essential step toward that goal. Beyond CCM, this work will be applicable to a range of other benign tumors and vascular lesions driven by PIK3CA mutation.”

Our team has had extensive experience conducting the first analysis of mutated genes in CCM lesions dissected
from humans and mice. We now propose to take this experience to the next level by working to develop biomarkers for PIK3CA mutations specifically. Currently approved projects in our lab do include funding to probe this novel development. We hence need pilot funds to support microRNA assessment from mouse blood. This pilot data and proof of concept would motivate a larger grant application to the NIH/NINDS to incorporate this novel biomarker in preclinical drug development and ultimately in clinical trials.

— Dr. Romuald Girard in the Neurological Surgery Department at the University of Chicago

Research Funding was provided for our 2021 Micro-Grant Cycle:

Be Brave For Life Research Summary 2021 Douglas McConnell, MD, FACS

(CCM = Cerebral Cavernous Malformations)

Project #1 We Need a New Mouse Model

There may exist a possible pathway for gene therapy for CCM. Focused ultrasound can be used to facilitate the delivery of biomolecules (Cas9 enzyme) that may interrupt or repair the cells that create and grow vascular malformations. There are several human clinical trials to explore gene therapy for systemic blood disorders such as sickle cell and Beta Thalassemia. CCM may be an excellent next candidate. However, to explore this we need a mouse model that develops human like CCM.

“To investigate experimental gene therapy for CCM in the mouse we need a mouse model that harbors a very comparable DNA defect to those found in humans”

IF we develop a mouse with CCM we can explore the delivery of targeted gene therapy

Project #2 We Are Looking for Clinical Biomarkers

Blood and tissue samples from brainstem CCM patients have already been frozen and await examination for long non-coding RNAs. These are known to play a role in the pathogenesis of cerebrovascular disease. One half of the needed patient samples are on hand. It is proposed to continue collecting the needed tissues from multiple centers and then test them for the long non-coding RNAs.These biomarkers MAY help in diagnosis and measuring therapeutic response if they are present.

Project # 3 A Possible Treatment For CCM

This is an ongoing exploration of the role of targeted inhibition of the oncogene (tumor causing gene) BMI1 resulting in blocking or reducing the formation of CCM in the mouse model. Phase one of this proposal is a “Proof of Concept” that this inhibition is efficacious. The original mice strain died in 10 days so now this noted CCM inhibition needs to be studied using a mouse model with longer survival. With the better mouse, they hope to prove efficacy AND test the size reduction (hopefully) of CCM using brain MRI. The lead investigator states “if successful, this project could lead to the first pharmacological treatment of CCM”. He also alludes to possible industrial partners to create a clinical pathway to treatment.

Note :

BMI1 Encodes for a protein that plays a central role in DNA damage repair. This gene is an oncogene and aberrant expression is associated with numerous cancers and is associated with resistance to certain chemotherapies

Research Funding Updates for our 2020 Micro-Grant Cycle:

Be Brave for Life awarded $101,000 in micro-Grants July 2020

Here are some Be Brave Grant highlights:

✦In 2019 Be Brave funded a collaborative project between The Barrow Neurological Institute, Duke University, and University of Chicago called the Evaluation of Oral Propranolol Therapy in a Mouse Model of Cerebral Cavernous Malformations (CCMs). We are excited to share that propranolol (a drug that is currently FDA approved for the treatment of hypertension) was effective for the treatment of CCMs in the mouse model. This study is the first definitive evidence demonstrating that oral propranolol is effective in the management of CCMs.

This year, Be Brave will continue to support this project’s next step, identifying a dose that has acceptable side-effects [for patients]. [Moreover,] establishing a well-tolerated, yet effective lower-dose limit is essential before applying for federal funding of a large multicenter clinical trial.

✦ UCSD medical school researcher Wenqing Li’s project will test beta-blockers in CCM treatment with animal models (zebrafish). Dr. Amy Akers explains, “The goals of this project are to tease apart the signal/receptor system related to beta-blockers to determine which drug in this class is most appropriate for the CCM Community. To approve a drug for treatment of a condition like CCM, the FDA requires a laundry list of data and supporting evidence. This project aims to provide a biological explanation to the anecdotal evidence that we currently have for propranolol treating cavernous angiomas. Additionally, the study may uncover additional drugs that may also become possible CCM therapeutics.”

✦The Institute of Pharm. Research in Milan, Italy is currently conducting a study funded by the Italian Agency of Pharmacology called “Treat_CCM.” According to Dr. Meessen, “In the study, patients were randomly allocated to receive propranolol or standard of care and they are monitored for 2 years in order to assess the effect of the drug on clinical events as well as on the evolution of the lesions as assessed by means of brain magnetic resonance imaging (MRI).” Our grant will bridge the gap between this study and an observational phase, thus allowing for insights into the mechanisms by which propranolol may alter the risks for clinical events, and lead to more clinical data, MRI-images and biological samples.

Research Funding Updates for our 2019 Micro-Grant Cycle:

University of California San Diego

Our research aimed to understand how cerebral hemorrhages occur during cerebral cavernous malformations also known as cavernous angiomas. Because brain bleeding is a significant cause of disability in patients living with cavernous angiomas, our research is using bioinformatics and Artificial Intelligence (AI)- based technology to help in the selection and development of non-invasive therapies to prevent brain hemorrhage.
We have discovered that during cavernous angiomas, there is a dramatic increase in factors that decreases blood coagulation (anticoagulant factors). These anticoagulant factors are notably low in healthy young cerebral blood vessels to prevent bleeding in the brain. Our observations have led to the idea that the notable increase in these factors may predispose the brain to bleed. New knowledge from this research is likely to have a significant and direct impact on further understanding of brain bleedings and cavernous angiomas. For example, what are the triggers that imbalance anticoagulant factors in the blood vessels of the brain? Can we re-establish low levels of anticoagulant factors in the affected blood vessels? These insights will have a significant and direct impact to episodes of hemorrhagic stroke, and this will ultimately aid in the development of non-invasive therapies.
In parallel to this work, we are currently using AI-enabled approaches to identify other key mechanisms responsible for the development and progression of cavernous angiomas. The Benevolent Knowledge Graph is being used to generate new target hypotheses around the selected mechanisms with the ultimate aim of identifying innovative ways to target the disease and reduce lesion burden in cavernous angioma patients.

–Dr. Miguel A. Lopez-Ramirez, University of California San Diego

International Neuroscience Institute (INI), Hannover, Germany

The following milestones have been achieved until date:
1. Based on the pre-operative symptoms, clinical history and MRI/CT scans, the patients were confirmed to be affected due to CCM in the brainstem by the senior neurosurgeon (Prof. Helmut Bertalanffy). The control subjects were subsequently selected with no prior clinical history of any cerebral lesions.
2. All the CCM patients and control subjects enrolled in this study gave their informed consent.
3. The blood samples (10 brainstem CCMs and 4 normal subjects without any brain lesions) were collected pre-operatively in 10 ml Streck cell-free RNA BCT tubes. This special collection tubes stabilizes the cell-free RNA in plasma up to 7 days at room temperature.
4. The plasma was isolated from the whole blood, aliquoted and stored at -80°C until total RNA isolation.
5. We are now isolating the total RNA from all the CCMs and normal plasma samples and the RNA quality control by Agilent Bioanalyzer 2100 will be performed thereafter.
6. Following quality control, the total RNA will be sent to Helmholtz Institute of Infection Research, Braunschweig, Germany for cDNA library preparation and RNA-sequencing.

–Dr. Souvik Kar, International Neuroscience Institute

University of Chicago

Some people have a disease called cerebral cavernous malformation (CCM). Some patients with this disease have bleeding in the brain. The mouse models of CCM disease have been used to understand this disease and help develop therapeutics to prevent bleeding or other clinical outcomes. In this project, we took blood samples from mice to measure the levels of specific molecules in the blood, including micro-RNA. Our first results show that the micro-RNA (mmu-miR-3472a for example) can differentiate the different genetic forms of the disease (Ccm1, Ccm2 and Ccm3). Down the line, we will try to assess these specific molecules in human patients with the disease. We hope that these molecules can be used to identify the genetic forms in patients, and could assess the effect of therapies.
1.  CCM disease can cause bleeding in the brain in human patients
2.  Mouse models of CCM disease can help to understand how the disease develop, and progress toward bleeding
3.  Some blood molecules called micro-RNAs can differentiate the different genetic forms of the disease
4.  These blood molecules could be used to identify the genetic forms in patients, and asses the effect of therapies Included a picture with update.

–Dr. Robert Shenkar and Dr. Issam Awad, University of Chicago

IFOM, Milan, Italy

Thanks to the support of Be Brave for Life, we have previously identified a small population of endothelial stem cells – that we named Cavernomas Initiating Cells (CIC) – which are responsible for the formation and development of cavernomas. These peculiar cells respond to Ccm3 deletion undergoing Endothelial-to-Mesenchymal Transition (EndMT) and uncontrolled clonal expansion to generate CCM lesions. These CICs can then attract the surrounding normal endothelial cells which contribute to the growth of the lesion. This process is comparable to the development of a non- cancerous vascular tumor with endothelial stem cells reacting to Ccm mutation, with hyper proliferation and formation of vascular malformations.
In this pilot project we tested the efficacy of a class of drugs which inhibit the proliferation as well as the EndMT selectively of stem cells with the aim of specifically target the Cavernoma Initiating Cells.
Indeed, the treatment with these drugs inhibited both the number and the size of lesions in a preclinical murine model of CCM.
If successful, this approach will open the possibility of a new pharmacological strategy directed to the cells responsible for the formation of cavernomas, minimizing the side effects on healthy cells, and therefore optimizing the risk-benefit balance.

–Dr. Malinverno, IFOM

Boston Children’s Hospital

Cerebral cavernous malformations (CCMs) are slow-flow vascular malformations with “leaky” endothelium, which clinically most commonly results in intracranial hemorrhage in both sporadic and
familial patients. Recent studies have demonstrated that cavernous endothelium undergoes an endothelial-to-mesenchymal transition by which endothelial-specific behavior is lost. We have been isolating
human brain endothelial cells from abnormal blood vessels (IRB consented protocol #10-417) and working to characterize axonal guidance factor signaling that has been implicated in the literature in endothelial-to mesenchymal transition. As part of the ongoing work, we have identified altered expression of EphrinB2 and EphB4 in primary patient derived cavernoma cell lines. We are now working to target axonal guidance factors through receptor blockade and over-
expression studies to further understand the implications of our findings.
This seed grant support has allowed us to make significant headway into better understanding a novel pathway related to cerebral cavernous malformation and this work has been made possible by the generosity of the Be Brave for Life Award. Since receiving this award, our work has been presented nationally and internationally at the Angioma Alliance CCM Scientific Meeting; Silver Spring, MD and the CCBIO-VBP Research Meeting (INTPART); Reykjavik, Iceland. Thank you again for all that you do to support research to treat cavernous malformations.

–Dr. Katie Fehnel, Boston Children’s Hospital

Centenary Institute, University of Sydney, Australia

Once again, thank you for your generous support for our research and all the important work the Be Brave for Life do for the community of patients and researchers. We have investigated the role of Ccm2l in CCM disease using state-of-art mouse genetic models. So far, our mouse studies have suggested the protective role of Ccm2l in CCM2 mutation induced CCM lesions. Deletion of Ccm2l have aggravated CCM lesions in our animal studies. However, Ccm2l appears to be redundant in CCM1 mutation induced CCM lesions as no affects have been shown.
We are expected to complete the study by early 2020 and the outcomes of our project will be submitted for a publication. Our study demonstrates an important role of Ccm2l in CCM disease and suggests further investigations to whether Ccm2l can be a novel therapeutic target to treat CCM lesions in patients.

–Dr. Peter Choi, Centenary Institute

Research Funding Updates for our 2018 Micro-Grant Cycle:

Collaboration: Duke University, University of Chicago, and the Barrow Neurological Institute

[Be Brave for Life] is funding this collaboration so researchers can use a mouse model of the CCM disease [created at Duke University] that copies the features seen in the human disease to […] identify a drug that will reduce CCM lesion burden and bleeding.

[For this research initiative they are testing the idea] of “repurposing” Propranolol [an existing drug currently used to treat infantile hemangiomas] for treatment of the CCM disease. Dr. Zabramski, from Barrow Neurological Institute, has treated a few CCM patients with propranolol that appear to have improved due to the treatment.Unfortunately, this sparse human data alone is insufficient to motivate a large clinical trial to test the medical use of propranolol. Therefore, the goal of this mouse study is to formally test propranolol in our newest mouse model(s) of CCM disease.  This group is currently treating two different models of CCM with propranolol to determine if it will decrease the size and/or number of CCMs (so called “lesion burden”) and in a slightly different mouse model, determine if the drug will decrease bleeding from the CCMs.  

— Douglas Marchuk, Phd Duke University School of Medicine

If this mouse study is successful, it could pave the way for potential funding by the NIH in the near future for a large clinical trail to test the medical use of propranolol to treat CCM in patients. To learn more, click here.

Angioma Alliance

We provided funding to support an upgrade to the Angioma Alliance’s first-ever patient registry for cavernous malformations,  The Susan Sukalich International Cavernous Angioma Patient Registry. This upgrade coincides with our mission to support innovate research with the potential to improve outcomes for people with cavernous malformations.  This registry makes it easier for researchers and doctors to find potential candidates for clinical trials like several of the ones we support.

This rebranding effort will unsure that the patient community is ready and available to contribute to finding better treatments for cavernous angioma and provide a model for other rare disease networks.

— Amy Akers, PhD, Angioma Alliance Chief Scientific Officer

Boston Children’s Hospital, Katie Pricola Fehnel, MD

[The Be Brave for Life] seed grant support has allowed [Dr. Fehnel] and her team to make significant headway into better understanding a novel pathway related to low grade glioma growth.  The hope is that this small proof-of-principle work, which had previously been outside the scope of other funding mechanisms, has now been expanded to enough data to promote a more robust, long-term grant application that will markedly increase the ability of our group to focus efforts on dedicated low grade glioma research.  The Be Brave for Life Award has had an impact by enabling [her team] to do critical initial studies that otherwise would be impossible.  

— Dr. Katie Pricola Fehnel

Centenary Institute, University of Sydney, Australia

The role of Adamts in Cerebral Cavernous Malformation (CCM) disease

With the Be Brave for Life micro-grant, I have identified a drug called Ponatinib which can strikingly prevent CCM formation and growth in our CCM mouse models. This is a significant as Ponatinib is already approved in clinics and currently used to treat cancer patients. Hence, I have re-purposed an existing drug.

My work has been published in a highly regarded scientific journal called Science Advances in November 2018. Meanwhile, I have been trying to find clinicians who can test Ponatinib in their CCM patients to see if this drug can treat CCM in humans. Part of the data generated from this project is used in my grant applications in National Health and Medical Research Council of Australia (NHMRC) which is NIH equivalent in Australia. I expected to find the outcomes of these grants by end of 2019.

-Dr. Peter Choi

To learn more, click here.

Collaboration between Mirrx Therapeutics, Centenary Institute, University of Chicago and Axolabs

Update anticipated by October 2019.

IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy

The Vessel-associated Endothelial Progenitor Cells: a new paradigm for Cerebral Cavernous Malformations origin?

There is an urgent need to investigate the mechanism of CCM to improve its treatment outcome in patients who indeed have very limited therapeutic options. Surgery and stereotactic radiosurgery represent the only line of treatment for CCM patients and no pharmacological therapy is currently available in clinic. In this project we propose a novel mechanism of lesion formation, which would open new therapeutic approaches. Using a transgenic murine model of the disease, we demonstrated that CCM lesions develop through the uncontrolled clonal expansion of a particular subset of mutated endothelial cells, the Cavernoma Initiating Cells (CIC). These mutated cells responsible for the onset and progression of lesions, can then recruit normal surrounding cells which in turn contribute to cavernoma development. This make CCM lesions be considered, for the first time, as benign tumors of the endothelium. This project paved the way to characterize CICs and easily distinguish them form the normal ECs opening the possibility to identify new target drugs, specifically acting on cells responsible for CCM, while minimizing the side effects on healthy tissues. This would be of impact for patients’ life expectancy and quality.

-Dr Matteo Malinverno

University of California – San Francisco Medical Center

Update anticipated October 2019

University of Chicago

Bridge Funding of CCM-Specific Research Database for Trial Readiness

The grant was used to help us meet the costs of constructing a cross-institutional database of patients with cavernous angioma’s and symptomatic hemorrhage (CASH). This type of database allows remote data entry from multiple institutions, an essential step for trial readiness initiatives. The data base is already being applied to a large NIH funded project, assessing screening and enrollment rates, and characteristics of CASH patients who might be enrolled in upcoming trials. The same data base is being applied for enrolling patients in the ongoing Atorvastatin CASH trial in Chicago. Individual projects, going forward, will fund the use of the database, but the cost of constructing and LAUNCHING g it could not be done without the bridge support.

-Dr. Issam Awad, University of Chicago

To learn more, click here.

Pilot Funding for Independent Sample Validation of Prognostic Plasma Biomarkers Predicting CCM Symptomatic Hemorrhage or Lesion Growth

The pilot funding allowed us to validate an initial discovery. Regarding blood levels of 4 proteins, that can predict which cavernous angioma patients might bleed in a subsequent year. This amazing discovery could lead to a blood test, identifying patients at risk of bleeding. With the pilot funds, we were able to duplicate the results in a separate patient sample, an essential step to validating the blood test. This is being published. Next steps are to test additional molecules that can help refine the blood test, and also to duplicate the results at multiple institutions. These plans are underway.

-Dr. Issam Awad, University of Chicago

University of Pennsylvania, PennCHOP

Progress report on studying the gut microbiome in CCM patients

We have been studying how the gut microbiome influences CCM disease; undergoing a collaborative, multi-institutional effort to recruit CCM patients and characterize their gut microbiomes. This is an important first step towards identifying gut microbiome-based biomarkers and developing long-term microbiome-based therapies for CCM disease. The initial results are highly promising and validate our previous laboratory findings. CCM patients harbor a gut microbiome distinct from that of the general population and we have identified specific types of bacteria that may be implicated in disease progression. This study, funded by the Be Brave for Life micro-grant, generated necessary preliminary data for two awarded NIH grants that will allow us to further investigate these intriguing findings.

(1- successful renewal of the Brain Vascular Malformation Consortium grant (Helen Kim, NIH NINDS U54 grant). 2. The award of a NIH SPIRiT grant (Issam Awad and Mark Kahn, NIH CTSA pilot grant).

These grants will allow us to continue our efforts to gather and characterize the gut microbiomes of more CCM patients with the objective of identifying biomarkers and moving towards microbiome-based therapies.

-Dr. Mark Kahn, University of Pennsylvania, Translational Research Center

2018: $150,000 in Micro-Grants Awarded

Angioma Alliance

The Angioma Alliance launched the first-ever patient registry for cavernous malformations in 2010 to create a communication tool to connect the patient and research communities with the goal of facilitating study recruitment. We’ve provided the funding needed for a platform upgrade to the Registry that will collect and provide standardized data directly to researchers, and to enable mobile device functionality for both participants and research partners.

There are twelve therapies currently under investigation in academic and industry labs [for CCM treatment]. As clinical trials progress, this upgrade will ensure that the patient community is ready and available to contribute to finding better treatments.

— Amy Akers, PhD, Angioma Alliance Chief Scientific Officer

Boston Children’s Hospital, Katie Pricola Fehnel, MD

This research project is designed to identify the key components that differentiate benign brain tumors from other cancers so that benign lesions can be better targeted. This grant will serve as a stepping stone to NIH funding.

Centenary Institute, University of Sydney, Australia

Despite recent advances, we still lack any targeted therapeutics to prevent or stabilize CCM lesions. This project, to determine if Adamts (a secreted, extracellular metalloproteinase) deletion can prevent CCM lesion formation, has great potential to set foundations to identify a new drug treatment for CCM patients where currently there are none.

Collaboration: Our recent work published in Nature in 2017 involving 15 different research groups from Australia, China, Europe and USA demonstrate for the very first time the link between stroke and gut microbiome. This work has attracted huge interest and attention around the globe as evidenced by numerous media articles including the New York Times.

— Jaesung P. Choi, MD and Xiangjian Zheng, MD

Collaboration between Mirrx Therapeutics, Centenary Institute, University of Chicago and Axolabs

This group has developed a Blockmir CD5-2 that may be used to treat CCM.  This funding will provide for patient tissues and matched normal tissues to be investigated.  This group has substantial data showing they can reduce existing lesions in both size and number.

To our knowledge this is the first compound able to not only prevent lesions from forming, but which can also reduce and possibly even entirely remove already existing lesions. […] We have substantial data showing that we can reduce existing lesions in both size and number in Cerebral Cavernous Malformation when we treat mice bearing CCM2 mutations with CD5-2. Our goal is to bring CD5-2 to the market as a novel treatment for CCM.

— Christina Udesen, PhD, Chief Scientific Officer, Mirrx Therapeutics

IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy

The project, The Vessel-Associated Endothelial Progenitor Cells: a new paradigm for cerebral cavernous malformations origin, is a concept study for the identification of a new mechanism for the pathogenesis of CCMs, through which cavernomas would be considered, and likely treated, as benign tumors of the endothelium.

This project has the potential of creating a pioneer and innovative approach to identify new and specific pharmacological therapies to treat this disease.

—  Matteo Malinverno, senior post doc in Vascular Biology Unit

University of California – San Francisco Medical Center

The research pilot project evaluates circulating (blood) micro RNA as a potential biomarker of disease severity and progression in familial cerebral cavernous malformations, which may signal a need for treatment and guide clinical management of patients. Both negative and positive results from this pilot study will be informative and provide strong preliminary data necessary for a larger NIH grant proposal planned for submission in late 2018.

The impact of [this] study is two-fold. First, understanding of what determines CCM disease severity and rate of progression is lacking. Identification of biomarkers of disease severity will aid in mechanistic understanding of the disease, and in the development of more accurate disease prognosis and medical management…Second, there is a significant unmet need for medical therapies of CCM. Clinical trials of any novel or existing therapies require biomarkers to assess outcomes and monitor progression.

— Ludmila Pawlikowska, Ph. D

University of Chicago

Pilot funding for an independent sample validation of prognostic plasma biomarkers predicting CCM symptomatic hemorrhage or lesion growth provides gap support to leverage a much bigger investment by the National Institute of Health (NIH).

In pilot studies, we asked for the first time, the “million dollar” question, whether levels of the mechanistically relevant biomarkers in peripheral blood plasma can predict symptomatic hemorrhage or lesion growth in the subsequent year. This would be the holy grail of ultimate biomarker performance, a blood test that tells patients whether their lesion would grow or bleed, or not, in the near future. Our pilot results were recently presented at the International Stroke Conference in January 2018, and were nothing short of breathtaking.

— Issam A. Awad, MD, MSc, FACS, MA (Hon), University of Chicago Medicine and Biological Sciences

Bridge funding for the construction of VISION, the electronic data capture (EDC) system, a CCM-specific research database for trial readiness that focuses first on cavernous angiomas with symptomatic hemorrhage (CASH). CASH are the cases most likely to rebleed, experience cumulative disability, and disruptions in quality of life (QOL), and are most likely to enroll in clinical trials of novel agents.

We propose for the first time a harmonized multisite assessment of enrollment rates of CASH, determination of baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes and QOL in relation to clinical bleeds…The recent James Lind Alliance priority setting partnership conducted by Cavernoma Alliance U.K. identified among the top priorities for research several aims of this trial readiness proposal. Such a project has never been undertaken in a benign brain disease, and CCM will serve as a model in this regard.

— Issam A. Awad, MD, MSc, FACS, MA (Hon), University of Chicago Medicine and Biological Sciences

University of Pennsylvania, PennCHOP

This is a translational research project investigating the effects of the gut microbiome on cerebral cavernous malformation (CCM) disease in human patients. The goal of this project is to determine whether variations in the gut microbiome are associated with CCM disease severity.

The completion of this project will potentially validate a therapeutic approach to change the standard of care for hundreds of thousands of patients affected by CCM disease…Any findings may be broadly applicable to other neurovascular malformations.

— Dr. Mark Kahn, Professor of Medicine, UPenn

2016-2017: More Than $200,000 in Support

Boston Children’s Hospital (BCH)

We’ve provided over $100,000 to support Dr. Edward Smith’s laboratory efforts that focus on developing new tools to diagnose and treat diseases that cause tumors and strokes in children. Funded in part by the Be Brave For Life Foundation, Dr. Smith’s lab recently discovered that certain molecules—urinary biomarkers—when found in the urine, indicate the presence and progression of brain tumors and vascular diseases (such as AVMs and CCMs).

Dr. Smith has a particular interest in brain tumors, cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs) and moyamoya, as these are the conditions that most often affect the children he sees in his practice. Over the past few years, Dr. Smith and his team have developed specific biomarker panels that identify different types of disease. To date, his lab has developed unique diagnostic “signatures” for medulloblastoma, glioma, glioblastoma, juvenile pilocytic astrocytoma, AVMs, moyamoya disease, and Chiari malformations. These “signatures” enable increased diagnostic accuracy using non-invasive urine testing since, as Dr. Smith points out, “nobody likes needles, especially kids.”

Urine testing has unique advantages, in that collecting urine is non-invasive (no needles), does not require general anesthesia, sedation or radiation (like MRI or CT) and can be done at home (saving trips to the medical centers for imaging). In addition, urine tests are 10-100 times cheaper than MRIs, allowing for more frequent testing and savings for everyone involved. Most importantly, the use of urine testing for specific molecular fingerprints means that there is now a new way to test for the disease. The discovery of these molecular fingerprints can help identify new targets for treatment, in addition to improving diagnostic accuracy.

To be clear, researchers do not anticipate using urine tests to replace MRI or CT, but they hope that the development of this new technology will complement existing tools to make the identification and treatment of these challenging diseases more effective than ever before.

What is so special about what Be Brave For Life is helping to fund is that cerebrovascular diseases are often conditions that other bigger funding groups generally don’t want to touch.

— Edward Smith, MD

Barrow Neurological Institute (BNI)

Be Brave For Life has also provided $115,000 to support Joseph Zabramski, MD, and his team’s research into a new treatment for cerebral cavernous malformations (CCMs). While four decades of research into CCMs has resulted in a greater understanding of the growth of these lesions, treatment options remain limited. Physicians can manage a patient’s symptoms or remove the CCM(s), but not without potentially adverse neurological effects or life-threatening risks. Barrow neurosurgeons and researchers are working to change this by testing an oral drug that is believed to shrink and possibly eradicate CCMs, thus avoiding invasive surgery and improving outcomes.

This has been an exciting year for Dr. Zabramski and his research partners, Barrow’s Robert Spetzler, MD, Translational Genomics Research Institute’s Matthew Huentelman, Ph.D., and University of Utah’s Yashar Kalani MD, Ph.D. A number of clinical trials have demonstrated that propranolol (a low-cost and FDA-approved medication with a long history of widespread clinical use) can significantly shrink cutaneous hemangiomas in infants and that the drug is extremely safe in this population. Because of the similarities between cutaneous hemangiomas and CCMs, they have proposed that propranolol may be an ideal candidate for treating both types of lesions.

Based on initial positive research results using oral propranolol, published in the April 2016 issue of World Neurosurgery, and with financial support of Be Brave For Life, Dr. Zabramski and his team have continued investigating the use of oral propranolol in a small number of patients at Barrow who are unwilling or unable to consider surgical intervention.

Recently, the team presented a proposal for a Phase III clinical trial of oral propranolol at the12th Annual Scientific Meeting of the Angioma Alliance on November 10th, 2016 in Washington, D.C. The presentation entitled, “A Proposed Trial of Oral Propranolol for Symptomatic Cerebral Cavernous Malformations not Amenable to Surgical Resection,” was well received, and there is now international interest in this clinical trial. Following the meeting, Drs. Zabramski and Kalani met with the program director of the National Institute of Neurological Disorders and Stroke and National Institutes of Health, Jim Koenig Ph.D., to discuss government funding for their study. The team is also working with several groups in Italy to submit a joint funding request to the National Institutes of Health later this year

Further, Dr. Zabramski’s team recently completed necessary preparation and design for a clinical research protocol at Barrow which promises to provide insight into the mechanism of propranolol’s effect on CCMs. The research team expects to complete participant enrollment by summer of 2017. Knowledge regarding the potential mechanisms of propranolol’s effect on CCMs is essential to obtaining government funding for a Phase III clinical trial.