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Research News

Curated by Amy Akers, PhD, Angioma Alliance Chief Scientific Officer

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Angioma Alliance provides lay summaries of recently published cavernous angioma (cavernous malformation, cavernoma) research, and we report other research-related news. This page is organized by date, with the most recent information first. Please visit Angioma Alliance President and CEO Connie Lee's CEO's Corner for more Angioma Alliance program news.

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July 12, 2019

What is a cavernous angioma?

(Other terms for this lesion include cavernoma and cerebral cavernous malformation (CCM))

These lesions are often described as 'vascular malformations,' but are they really tumors? The answer is both - cavernous angiomas are made from blood vessels (endothelial cells) and have proprieties of both malformations and tumors. A recent study expands on what we know about the tumor-like qualities of these lesions.

In past work, Elisabetta Dejana's groups in Milan and Upsalla, Sweden have investigated the behavior of lesion blood vessels. Typically, blood vessels are pretty stable; they don't change shape or move. Their purpose (especially in the brain) is to hold tight to one another and keep blood inside the vessel. Within a cavernous angioma lesion, however, some of the endothelial cells take on different properties - they move, they become active and express a host of chemical signals that are different from their quiet neighbors.

Taking this work to the next step, the research team sought to understand how these behavioral changes are related to lesion formation.

A hallmark feature of tumors is growth by a process called clonal expansion. This is where a cell gains some sort of advantage (often due to a mutation) that causes it to replicate over and over and over again in an unregulated fashion. The result is a mass of identical cells that can become a tumor.

This study team used mouse models to show that when brain blood vessel cells lose complete function of one of the CCM genes (in this case, CCM3), that cell multiplies itself in a clonal fashion and seeds the formation of the cavernous angioma lesion. The Marchuk Lab at Duke University also published similar findings late last year (Detter et. al, 2018). Essentially, the first step in developing a cavernous angioma is to create a small vascular tumor by the process of clonal expansion.

Details & Definitions - In this experiment, the cells that undergo clonal expansion have two mutant copies of CCM3. These two mutations together cause complete loss of function of that gene. We will call these cells, Ccm3-/-. By comparison, Ccm3+/- have one mutant copy of the gene, and Ccm3+/+ are known as 'wildtype' and have no mutations in the CCM3 gene.

Now, interestingly, cavernous angioma lesions are not composed entirely of clonal Ccm3-/- cells. Dr. Dejana's team also showed that the double mutant (Ccm3-/-) cells start the formation of the lesion, AND they are also able to recruit other neighboring cells into the developing lesion.

There is a great video (like below) that shows a visual depiction of cellular behavior. The left panel shows how wildtype (green) blood vessel cells typically grow in a flat layer, not 3D clusters. On the right, you can see the Ccm3-/- (red) cells quickly multiplying and grouping into clumps. Then, towards the end of the video, you can see the green (wildtype) cells are drawn into the cluster. This experiment was done in a lab using a cultured cell line grown in a dish, but, this data is a surrogate for what we can expect to happen in the brain.

(Link for the video: https://www.ncbi.nlm.nih.gov/…/41467_2019_10707_MOESM10_ESM…)

These findings help to expand our knowledge related to the cancer-like properties of cavernous angiomas, and what types of cells are included within the lesion itself. Dr. Dejana's work is published in Nature Communications and is available here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591323/

These results may lead us to new ways of thinking about treatment targets and/or prevention of lesion genesis.

 

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June 26, 2019

New research aims to help clinicians determine whether their patients have experienced a recent hemorrhage; and, this new method does not require an MRI!

A challenge faced by physicians and patients alike is the desire but inability to predict the behavior of CCM lesions - we all want to know if and when a bleed is most likely.

Over the past few years, Dr. Awad's team at the University of Chicago has spearheaded several efforts to develop biomarkers (alternative ways to measure disease severity and/or predict/measure bleeding, for example). Last year this team published on the development of a prognostic biomarker for hemorrhage. They showed that by measuring the relative abundance of several inflammatory molecules in the circulating blood, it is possible to predict whether or not an individual is likely to experience a hemorrhagic bleed event in the coming year.

This new study takes the next step. Understanding the integral connection of inflammation to past and future bleeding, Dr. Awad's team sought to determine whether they could develop a DIAGNOSTIC biomarker that similarly measures relative levels of inflammatory molecules. By combining this biological knowledge with machine learning, they demonstrated that by measuring a unique set of molecules in the blood plasma; one can determine whether or not an individual has experienced a bleed within the last year.

With proper validation, these diagnostic and prognostic biomarkers may be useful tools for routine care and clinical trial recruitment as they can help to clinically stratify levels of bleeding risk. The next steps for research will likely involve a larger study with more participants to refine the results. These findings may also lead to further exploration of biological connections of the measured inflammatory molecules to understand better how they are related to cavernous angioma bleed.

The original publication is published in JCI insight and is available HERE.

 

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June 4, 2019

A new study highlights the challenges and opportunities associated with gene therapy for cavernous angioma.

 

The CRISPR/Cas9 system is a genetic tool borrowed from bacteria and developed by scientists to modify genes. In bacteria, CRISPR/Cas9 is a set of molecules that work in concert with the immune system to identify foreign DNA from viruses and fight off infections. Repurposed for research, CRISPR/Cas9 is now a powerful tool that scientists use to precisely correct gene mutations. Therapeutic implications are curative treatments for inherited diseases.

This new technology and promise of gene therapy for genetic diseases is not without its challenges. In the case of cavernous angioma, the tissue type that needs genetic correction is the cells of the blood vessel, endothelial cells. Endothelial cells are notoriously challenging to work with in the lab; they do not grow well and are difficult to modify. Gene therapy requires growing and modifying cells in the lab and then re-introducing those corrected cells to the host system.

A German research team led by Dr. Ute Felbor recently showed they could grow and genetically alter patient-derived endothelial cells that carried a CCM1 gene mutation. The experiment worked in two ways:

1. The team aimed to correct the mutation. This worked! A percentage of CRISPR/Cas9 treated cells were cured of their CCM1 gene mutation.

Over the last several years, we have learned that lesions develop in familial cavernous angioma due to the inheritance of one copy of a mutant CCM1, CCM2, or CCM3 gene AND the development of a sporadic (randomly occurring) mutation of the other copy of that gene in a blood vessel cell. This cell that has two mutant copies of one of the CCM genes develops a growth advantage over its neighbors and starts to replicate over and over and to seed the formation of a lesion.

2. The second part of the study was designed to investigate how the cells behaved if the scientists induced a second mutation to the wildtype copy of CCM1. They confirmed what I just described, by completely destroying CCM1 function in the endothelial cells, those cells gained a survival advantage that allowed them to grow and grow. This growth advantage is similar to the findings in CCM3 mice recently, where researchers showed that the lesion tissue grows by clonal expansion, like a tumor.

Taken together, these findings are important steps to show the feasibility of correcting CCM genes within the diseased tissue, and to confirm the cancer-like behavior of cells with complete loss of CCM1 function.

Challenges remain for therapeutic applications, however. Because of the difficulties associated with endothelial cell research, only a percentage of treated cells acquire the gene correction. To be a truly curative therapy, higher levels of efficiency of gene modification should be achieved.

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May 2, 2019

Transcriptome analysis generates a data library confirming past findings and driving new research for cavernous angioma. 

When you think about cavernous angioma research, I'm guessing the first thing that comes to mind is NOT using teeny tiny nematode worms to solve complex biological problems, right? Well, that is just what Dr. Brent Derry's team at the University of Toronto is doing...

Dr. Derry's lab has had a long-standing interest in the regulation of apoptosis. This is the tightly regulated and coordinated system of cell death that selectively kills damaged dells - a normal and necessary process for healthy living. The worm is fast growing with well-understood genetics, making this animal model is ideal for studying cell death.

How does cell death relate to cavernous angioma? Well, about 15 years ago Dr. Derry entered the cavernous angioma research space because he identified the worm version of the CCM1 gene and found it to have a critical role in apoptosis in the worm.

Fast forwarding to today, his team of trainees and collaborators recently published an article describing several new important findings:

  1. They found the worm versions of the CCM2 and ICAP genes (ICAP is another gene that codes for a protein involved in CCM1 signaling). These findings demonstrate the CCM1 signaling is essential and conserved across species, all the way down to the worm. Furthermore, these findings open doors to expand upon studies of CCM2 and ICAP in the worm.
  2. The paper also reports a unique connection to zinc. It is previously known that the distribution and the relative amount of zinc is also a regulatory feature of apoptosis. This study sought to identify and understand all of the pathway components related to CCM1 and apoptosis. From a series of genetic experiments, the team discovered that worm CCM1 regulates a zinc transport gene. When the regulation is disrupted, improper zinc storage contributes to the interference of normal apoptosis.

The team sought to confirm the zinc connection in other species and found that in zebrafish, mice, and human CCM surgical samples, CCM1 gene mutation also affects the proper function of zinc transport genes.

In summary, across the species, there seems to be a connection of CCM1 function and zinc regulation. How zinc impacts cavernous angioma disease biology remains unknown, however, and warrants further investigation.

Here is a link to the summary published by the University of Toronto, and here is a link to the full paper that is published open access in the prestigious journal, Nature Communications, https://www.nature.com/articles/s41467-019-09829-z.pdf.

 

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April 2, 2019

Transcriptome analysis generates a data library confirming past findings and driving new research for cavernous angioma. 

Scientists tackle CCM research from every angle. One approach includes investigating protein function and asking, What consequences result from CCM gene mutation? What other proteins work together with the CCM proteins, and how are their functions affected by CCM gene mutation? Using this strategy over the past few years, we've learned a lot about the biology of cavernous angioma and identified several targets for drug therapy.

A recent publication takes a different approach. The University of Chicago team wanted to know what genes are uniquely active in the cells that make up CCM lesions. They were able to address this question by isolating RNA from lesion tissue and analyzing those messages. (RNAs are the chemical messages that follow the directions coded by genes to create proteins)

The team compared messages from human lesions (both familial and sporadic) as well as mouse and worm models of cavernous angioma. The result is a fantastic (and quite extensive!) library of data. This dataset highlights biology that is specific to CCM1 or CCM3 lesions, for example. This data library can also be used to confirm past findings, to understand commonalities between species, to facilitate hypothesis generation, and point to relevant research spaces needing further investigation. These basic research findings help drive us toward our ultimate goal of clinical trials and successful treatments.

The full-length paper published in the Journal of Clinical Investigation JCI Insight is available HERE.

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March 13, 2019

New research shows promising results for the cholesterol-reducing drug, atorvastatin, as a possible therapy for cavernous angioma. 

In mice, treatment with atorvastatin reduced lesion burden (number and size of lesions) as well as chronic bleeding. These findings from the collaborative Duke and Chicago research teams provide additional support for the need to carefully investigate the effects of this drug on human cavernous angioma patients.

Atorvastatin is currently in clinical trial for the treatment of cavernous angioma with symptomatic hemorrhage. For more information and to learn if you may be eligible to participate, please visit this PAGE.

You can read the detailed abstract from the Journal Stroke, HERE

 

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February 12, 2019

UCSD researchers show us the importance of coagulation factors in relation to cavernous angioma hemorrhage.

Much of what we know about CCM lesion biology and drug targets comes from studies of the diseased tissue - blood vessels (made of endothelial cells). Our current thinking is that an inherited CCM gene mutation causes a disruption of neighboring endothelial cell junctions, resulting in lesion blood vessels that are structurally unsound and that have increased mobility and activity levels, uncharacteristic of typical blood vessel cells.

In a recent study, Dr. Ginsberg's team at the University of California at San Diego identified an increased activity of anticoagulation factors (those that prevent clotting) in response to CCM gene mutation. This finding led them to further investigate coagulation, as it relates to the biology of cavernous angioma.

In the plenary paper published in the Blood Journal, the study team addressed the question - does increased levels of anticoagulation factors lead to hemorrhage in CCM?

They found two anticoagulation components, thrombomodulin (TM) and endothelial cell protein C receptor (EPCR), that are associated with CCM biology. Both molecules are present at elevated levels in lesion tissue. TM concentration is also at elevated levels in blood plasma of cavernous angioma patients.

In mouse experiments, hemorrhage is associated with TM level (more TM (less coagulation) = more hemorrhage). Genetic experiments to decrease TM production (reduce the amount of protein in the blood vessels), results in a reduction of hemorrhage in CCM mutant mice. Additionally, CCM3 mutant mice, which otherwise would begin bleeding just nine days after birth, show reduced hemorrhage with an antibody-drug treatment that blocks TM activity.

Taken together, these findings show us that anticoagulation is a component of CCM biology. Targeting this system, either alone, or in combination with therapy for the endothelial cells, may provide a new opportunity for drug development.

Thrombomodulin may also serve as a useful biomarker to predict hemorrhage. Given the association of blood plasma levels of this molecule and hemorrhage, with more research, measuring TM could identify those individuals at greatest risk for future hemorrhage event.

The paper made the cover of the January 2019 Blood Journal. You can read the abstract of the paper, HERE

 

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January 22, 2019

New tools developed for surgery on deep lesions

NICO Corporation is a company that develops minimally invasive surgical technologies. BrainPath is one such system used to access deep CCM lesions, as described in this recent publication, available HERE.

 

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January 8, 2019

Furthering the Cancer Connection with CCM3

A team of genetic and cardiovascular disease researchers in Germany recently used CRISPR gene editing technology to develop a cell model that is completely deficient for CCM3 protein. The model is unique because the gene editing ensures the CCM3 deficiency is permanent, whereas other technologies may result in localized or short-term changes. The idea is that these cells, derived from human blood vessel cells, would behave most like those brain blood vessels in human patients that seed the formation of CCM lesions.

This new model supports other recent findings that CCM lesions have a cancer-like behavior. Like cells of a tumor, these cells, that have a long-term deficiency of CCM3, are able to survive longer and replicate faster than cells with some or full function of CCM3. Furthermore, these cells don't sprout and make branches as blood vessel cells should. Instead, they just replicate themselves over and over, likely contributing to the development of CCM lesions.

The authors of this study propose that this cell model might be useful in the future for testing novel therapeutics aimed specifically at CCM type 3.

You can read the entire article from the Journal of Cellular and Molecular Medicine, HERE

 

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November 8-9, 2018

2018 CCM Meeting Summary

The 2018 CCM Meeting continued on a great tradition of success – for the first time, we had over 100 attendees with representatives from five continents, five drug companies, three advocacy organizations, government officials and an international consortium of clinicians and scientists. 

An overview of the meeting proceedings can be found HERE

 

 

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November 9, 2018

National Family Conference Presentation

It was my pleasure to deliver a presentation to the family conference attendees about current research studies, particularly focusing on those recruiting participants. My presentation slides are available HERE.

 

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October 4, 2018

Intestines & CCM1 Protein 


CCM1 protein has important functions outside of the brain.

Recent studies from the team at the University of Chicago find that KRIT1 is important to maintain proper barrier function in the cells lining our intestine. (The CCM1 protein is called KRIT1. The intestine is lined by a layer of epithelial cells.) Interestingly, the way KRIT1 regulates control of permeability in the intestine is unique from the way the protein regulates permeability in brain vessels. In the brain, mutation of CCM1 result in stress fibers forming inside with cell causing a change in physical structure, and these changes can be reversed with ROCK inhibitor drugs. Neither is the case in the epithelial layer of the intestine, highlighting the diverse roles of this multi-functional protein. Continued research in this area may shed light on how CCM1 mutations may be related to other inflammatory or gut-related diseases.

This article was published in the FASEB Journal, the abstract is available HERE.

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September 28, 2018

Reactive Oxygen Species, Oats & CCM 


Oats and oatmeal-derived products (think anti-itch soaps and shampoos) have long been known for their calming, anti-inflammatory and anti-itch properties. In recent years research teams have dissected the molecular characteristics of oats and identified compounds directly responsible for blocking inflammation and cell growth, and for neutralizing reactive oxygen species (ROS). For example, drugs derived from related compounds are used as anti-histamines to treat a variety of allergy-related ailments, including atopic dermatitis.

What does all this have to do with cavernous angioma? Last year, a collaborative team from the University of Torino, Italy and the Unversity of Rochester published findings on an important connection between CCM1 gene mutations and the increased production of reactive oxygen species (ROS). (https://www.nature.com/articles/s41598-017-08373-4) Excessive amounts of ROS can be damaging to cells. In the case of CCM1, these extra ROS molecules contribute to leaky blood vessels of CCM lesions. This study team was able to reverse the cellular effect of ROS using an oat-derived anti-oxidant molecule.

Now, we aren't ready to make any clinical recommendation of oat-therapy for CCM. But, this review highlights the importance of continued research into oat-derived molecules for a wide range of illnesses, including CCM, that are impacted by inflammation or antioxidants.

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September 24, 2018

CCM Lesions Develop (in part) like a Tumor

New research highlights the cancer-like quality of CCM lesions...

The illness in which Angioma Alliance keenly focuses is known by several names - Cavernous Angioma and Cerebral Cavernous Malformation (CCM) are terms often used interchangeably. Angioma implies a cancer-like quality or vascular tumor. While the term malformation is distinctly noncancerous. A traditional malformation grows only as the body grows in size, not independently, like a tumor.

Well, the research team at Duke University have used genetically engineered mice and advanced microscopy to show that from the earliest stage of development, CCM lesions (in the familial form) start with a random (somatic) mutation to completely destroy the function of one of the CCM genes in a brain endothelial cell. This mutational even changes the cell such that it starts to grow, and grow, and grow (through a process of cell division and duplication)... As it becomes a mature multi-cavernous large lesion, those mutant cells also recruit non-mutated blood vessel cells into the lesion.

The biological significance helps us understand better how lesions develop and identify new targets for future therapeutic intervention.

The video is a 3D reconstruction of a mouse CCM lesion. The green cells are all derived from the same parent that has two mutations in CCM3, while the yellow cells are from another mutant parent cell with two mutations, resulting in complete loss of function and lesion development. The video is of two neighboring mature ccm lesions, each derived from a unique somatic (random) mutational event.

The study was published in the journal of Circulation Research, the abstract is available HERE.

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September 4, 2018

International Collaboration Identifies FDA Approved Drug as Possible CCM Therapeutic 

A collaborative research team from Canada, Germany, and France combines the strengths of worm, fish and mouse biology with large dataset analysis to screen a large number of compounds and identify a potential new drug for the treatment of CCM.

The goal of the project was to identify druggable targets that are shared between multiple animal models of CCM disease. Those with the highest level of biological conservation may be more likely to translate to the human condition.

The research team screened thousands of compounds (previously approved drugs that, with promising results, might be repurposed for CCM therapy) in worm and fish models to identify candidates. Those candidates were then tested in human cell lines and then mouse models of CCM.

Focusing specifically on drugs that have previous safety profiles of long-term use with minimal side effects and that biologically interact with more than one known CCM-related chemical pathway, the team identified several molecules including, IR3mo as a CCM drug candidate. IR3mo is a derivative of indirubin which is the active ingredient in traditional Chinese medicine. IR3mo is currently approved by the FDA for use as a leukemia drug.

The final phase of this study included mouse testing. Acute CCM mouse models are genetically engineered to develop lots of lesions at a very early time of life (within a few days). Treatment with IR3mo significantly decreased the number of lesions in these mice.

The full text of this journal article is available online.

 

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July 19, 2018

Dr. Awad Explains Two New Studies

New webinar available about clinical trials for cavernous angioma!

In his presentation, Dr. Awad shares information about clinical trial phases, preparation for large multi-center studies, and how to participate in the new Atorvastatin Treatment Trial for Symptomatic Hemorrhage of Cavernous Angioma.

The video recording is available on youtube (as below), with more information about the trial readiness and atorvastatin studies on our website.

Watch Dr. Awad's WEBINAR on our youtube channel.

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July 10, 2018

Recursion Pharmaceuticals Receives FDA Clearance for Phase I Safety Trial


Making progress toward clinical trial! Recursion Pharmaceuticals @Recursionpharma announces they have achieved a regulatory milestone for the drug REC-994 (tempol) and plans to begin phase I safety trials later this year.

For more information, read their press release.

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May 2018

Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Clinical trial is now enrolling. 

Read more

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October 2017

New Therapeutic Target. UCSD researchers identify Thrombospondin 1 (TSP1) as a possible therapeutic to inhibit CCM lesion development. 

Read more

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September 2017

Dr. Awad's team at the University of Chicago develops biomarker tools to facilitate the success of future clinical trials. 

Read more about plasma and imaging biomarkers.

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August 2017

BioAxone BioSciences is awarded an additional $1.5M in NIH funding to accelerate their drug development program for BA1049. 

Read more.

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May 2017

New Therapeutic Target. Researchers at U Penn discover a connection between gut bacteria and CCM disease severity. 

Read more in a New York Times article and on our microbiome research information page.

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October 2015

Recursion Pharmaceuticals obtains orphan designation for CCM

Read more.