2012 Scientific Meeting Update–Moving Towards a Cure

With 65 registered attendees from academia, industry, the medical community and government agencies, the 8th annual Angioma Alliance CCM Scientific Meeting was the biggest yet and the quality of the science presented was exceptionally high!  People from all over the world attended the preeminent meeting about CCM which could not have happened without Angioma Alliance.

We are so grateful to everyone who gave their time to attend the meeting, freely shared their data, engaged in lively discussions, and worked to foster new collaborations.  The meeting included presentations from basic and clinical scientists.  Session topics included: Proteomics, Protein Structure & Function; Signaling; Vascular Biology & Inflammation; Lesions Genesis; Magnetic Resonance Imaging Techniques; and Clinical Studies.  Much of the data presented was new and unpublished; therefore we are unable to report specific results from the presentations.  Here is a general summary highlighting a few important advances that have happened in the past year.

The field of CCM research is still relatively young and there are far more questions than answers.  One important question is, what are the functions of the CCM proteins?  That is, what do they do in the cell and why do they cause CCM lesions when they are mutated?  To address this, a number of groups have taken a structural biology approach to better understand the physical shape of these molecules.  Knowing the structure allows researchers to identify new interacting partners and uncover previously unknown functions.  We are learning that these molecules have many important roles in the cell.  How these different roles affect CCM disease remains unknown.  By studying all the functional roles of the CCM proteins, researchers may be able to identify new drug targets.  This line of research may also lead to better understanding of how treatments will affect sporadic versus familial disease and whether or not treatments will be effective for all of the CCM gene mutations.

Translating research findings from the laboratory to clinical treatment is a key priority and mouse models are essential to this process.  Researchers must demonstrate clinical effectiveness of a drug on mouse models before any testing can be done in humans.  It has taken many years to refine the CCM mice to be an effective tool for treatment studies.  The mice being used now develop CCM lesions like human patients and develop lots of them.  Having lots of lesions is important for treatment studies because it will be easier to see if a treatment is working.  Updated results with the Fasudil treated mice continue to be very promising.  In the future we look forward to leaning about how statin treatment and other drugs affect mice.

As we continue to think about moving laboratory findings and mouse studies toward treatments for the human disease, we need to have a good way to measure potential drug effects.  In cancer, one can determine that a drug is effective if the tumor stops growing or goes away.  With CCM, it is not that simple…we want a drug that stops lesions from developing (particularly in familial cases where multiple lesions are common), we want a drug that stops bleeding from happening, and we want a drug that stops lesions from growing.  How can we measure these things?  We don’t want to just wait for a bleed to know.  New magnetic resonance imaging (MRI) techniques are being developed specifically to address these questions non-invasively.  These techniques will likely be very useful tools in clinical practice for monitoring personal health and wellness and also as we look to the future of clinical trials.

Clinical trials were the focus of a group Panel Discussion that closed the meeting.  We chose to focus the last two hours of the meeting on this topic and use the CCM Meeting as a venue to bring together all of the important stakeholders who are needed for a successful clinical trial.  Those stakeholders include patient advocates (Angioma Alliance), researchers, clinicians, as well as representatives from the Food and Drug Administration (FDA) and National Institutes of Health (NIH).  In this discussion we talked about:

  • Biomarkers – Using MRIs to measure drug effectiveness
  • Recruitment – How to effectively advertise and enroll a large number of patients in a multi-site study.
  • Funding – How can the NIH help to fund a clinical trial for CCM.
  • Regulatory – What is the FDA regulatory process and paperwork needed for a trial, and how can Angioma Alliance help?

Importantly, we also discussed feasibility of starting a CCM trial from the science perspective – are we ready to move ahead with Fasudil, should we wait for statin results, would another drug be better?  These are all extremely difficult questions to answer.  At this time, although the Fasudil research is looking very promising and we are anxious for the statin results, neither drug is ready to move to human treatment studies quite yet.  Stronger evidence of effectiveness in CCM1, CCM2 and CCM3 is needed and those data are being generated currently.

We are definitely on the right track and Angioma Alliance has brought all of the key players together.  Each year we see the research growing at a faster pace.  People with CCM can now have hope that human drug trials will start in the not so distant future. Just three years ago we couldn’t have said that.  Together, with these scientists, we will find a cure!

Summary provided by Dr. Amy Akers, Chief Scientific Officer, Angioma Alliance

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Notes from the Road #1

I’ve been on the road with Julia for four weeks now and it’s time to offer an update of our journey. We’ve been having a wonderful time meeting families in Florida, Mississippi, and Texas. Today, we’ll be attending a get together in Phoenix that should be attended by a dozen people.

Our meetings have been powerful. For some people, this is the first time they’ve ever met anyone else with the illness. In Mississippi, we even brought together family members that had never met!  The get togethers have given folks a chance to share stories, compare doctors, and discuss the future. Some people are planning to organize other events including fundraisers in their areas.  Everyone has left committed to joining our patient registry and to encouraging affected family members to register (www.angioma.org/registry).  Below are some pictures from the trip:

The road trip begins with Charlie and Charlise, the Traveling Cavernous Angioma Awareness Bears

Julia visits with Ethan and Evan in St. Augustine.

Julia presents AJ Buscemi with Charlie the Bear in Tampa, Florida.

Cousins Melessia Bass (2nd from left) and Jerry Bowlin (2nd from right) meet for the first time in Kiln, MS.

Diana George and Jo Macaluso give hugs in Austin, TX.

Some of our friends in Houston: Diana Rodionov, Julia and Connie, Delia Barney, and Julien Bruce

More pictures to come as the trip continues. After Phoenix, we’ll be in Bakersfield on February 25th, Pasadena on March 10th, and in the San Francisco area on March 18th. Look for the entire itinerary at www.angioma.org/roadtrip.

See you soon!





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January 2012 Letter to the Community

January 17, 2012

Happy New Year from Angioma Alliance!  The Board of Directors wants to let you know about the plans that Angioma Alliance has for 2012. It is an exciting time for both Angioma Alliance and all those affected by cavernous angiomas as the scientific community moves closer to finding a cure. The statement “Without you there can be no cure!” has never been more true than now.

A major initiative for the coming year will be our 1200 in 2012 campaign. It is our goal to have 1200 participants in The International Cavernous Angioma Patient Registry by the end of 2012. As we start the year, there are 385 people who have taken the time to register. To reach our goal, we need your help! If you have cavernous angioma, please register today at www.angioma.org/registry. Also, please encourage family members and friends with cavernous angioma to do the same. The patient registry will allow researchers to quickly identify people who may be willing to participate in studies to see if medications can prevent the potentially devastating effects of active cavernous angiomas.

We also expect 2012 to be a year of further growth of Angioma Alliance Action Groups. Action groups are intended to create ways for our members with similar characteristics, such as location of lesions or geographic location, to come together. Our first Action Group, CCM3 Action, is making good progress toward setting up a clinic for those with the CCM3 mutation, has created a website and promoted networking. For more information about Action Groups, please see the Fall 2011 newsletter archived on our website at www.angioma.org/documents/2011FallNewsletter.pdf

A change this year will be the transition of Connie Lee, Angioma Alliance Founder and President, to the role of Ambassador/Founder as of January 31, 2011. She will also move into the Program Coordinator position with CCM3 Action. Connie founded Angioma Alliance after her daughter Julia was diagnosed with cavernous angiomas when only four months old. At that time, very little was known about the disease. Under her guidance over the past decade, Angioma Alliance has created a thriving peer support network, developed the International Patient Registry, provided support for research through our DNA/Tissue Bank, and raised awareness about the disease nationally and
internationally. The passion and unwavering devotion of a mother has resulted in an organization that is now the premier advocacy group for those with cerebral cavernous angiomas.

As Connie steps into the role of Ambassador, she and her 12-year-old daughter Julia are
launching a six-month road trip on January 21st to raise awareness of the disease and encourage enrollment in the Patient Registry. According to Connie, “The problem we have right now is finding people to participate in drug trials. While Angioma Alliance has a patient registry, it’s not growing fast enough. Julia and I will be traveling around the United States to raise awareness of the need for patients. We plan to visit with affected families and plant seeds to create local networks for mutual support and research
participation. The goal of Angioma Alliance is to register 1200 patients in 2012. We think we can help with this.”

Connie and Julia will first travel south from Virginia. Our website, www.angioma.org, will have information about Connie and Julia’s travels including an itinerary and updates on our blog. They would love to visit individuals and groups interested in Angioma Alliance. To arrange a visit or show your support, contact Connie via email at clee@angioma.org .

As Connie makes her transition to Ambassador, the Board of Directors of Angioma Alliance will continue to oversee the organization and build upon the excellent
foundation that Connie created over the last decade. The Board would like to extend a heartfelt thank you to Connie for founding and growing Angioma Alliance. Truly, the whole Angioma Alliance community is indebted to Connie. Without Connie, there would be no Angioma Alliance! We are grateful that Connie will continue to support and represent Angioma Alliance in her roles of Ambassador and Program Coordinator
of CCM3 Action.

2012 is also the year that you become more involved with Angioma Alliance. Please sign up for the Patient Registry today. Consider starting an Action Group, organizing a fundraiser or attending a get together with Connie. Remember, without you there can be no cure!

Best Regards,

Sara Sukalich, MD

Chair, Angioma Alliance Board of Directors

On behalf of the Board of Directors

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The Take Away Message from the 2011 Scientific Workshop

The big topic of this year’s workshop was treatment. Angioma Alliance, as an organization, is committed to being part of an international consortium for clinical drug trials.  There are many roles that we will play, but foremost is our obligation to provide participants for trials. As I wrote in the final day summary on the blog, we were told it would take, at a bare minimum, 1500 people, and this is if we are willing to spend extra time pre-testing medications before human trials. If we want to start sooner, we need more people – 30,000 isn’t too many. If everyone who is eligible for a drug trial were to register today in our online Patient Registry, there would be no delays for additional animal testing, no difficult decisions about which medications not to test. Scientists wouldn’t have to feel like they have just one shot to get it right. We’d start working on getting a trial approved tomorrow. While I am very grateful to everyone who has taken the time to register, at this point, the lack of registered potential participants is the obstacle that is causing the most concern and is potentially the most disruptive.

This is Thanksgiving week in the United States, a time when families come together. Please consider using this family time as an opportunity to discuss the importance of participating in finding a cure with every affected member of your family. Heck, set up a laptop in the den near the TV and make sure everyone gets a chance without having to miss a play. Want to find a way to end that conversation with cousin Earl? Try “Oops, look at the time. Let me see if it’s my turn to register.” Same is true if you are trying to get out of that Thanksgiving chore. “Sorry, I can’t wash those pans right now. Gotta register.”  If you live outside of the United States, don’t wait for your next family reunion – register today. It takes no more than 10-20 minutes to fill out the Patient Registry form at www.angioma.org/registry.  My Thanksgiving wish would come true if we could announce to the scientists on December 1st that hundreds more of us have stepped up.

It would be tragic if what held up a non-invasive treatment was not science or money or bureaucracy, but rather us and our unwillingness or apathy. For common illnesses, it is quite possible to sit back and wait for other patients to participate in trials. For cavernous angiomas, there just aren’t enough eligible people to allow anyone with a cavernous angioma to play the waiting game. We’ve been adding “Without you, there can be no cure” to many of our messages this year. I’m not professing to speak for everyone in leadership in the organization, but I mean that statement literally. If you have a cavernous angioma and choose to sit back, there will be no cure. Period. It really is that simple. Now go register. And have a great Thanksgiving.

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The Final Day of the Scientific Workshop

The first presentation of the morning was entitled “Cavernous malformations of the human brainstem: quasi-automatic three-dimensional-reconstruction from a stack of serial histological slides with a computerized technique” by François Chapon of CHU de Caen. François demonstrated how he is able to create a computerized 3-D model of a cavernous angioma and surrounding tissue from an excised lesion. This allows for very fine virtual examination of lesions including understanding how lesions are related to nearby vessels and whether they are, indeed, one connected group of cells. This was followed by a last minute addition to our program by Phillipp Dahmann of Euisberg-Essen who presented on the use of 7 Tesla SWI MRI to examine lesions.

Our two United Kingdom presenters, Jonathan Berg and Rustam Al-Shahi Salman, addressed the quality of the data that we have on cavernous angioma patients and treatment. This was followed by a short discussion of the need to find ways to integrate existing patient registries so that we are collecting a consistent set of information.

This launched us into a joint presentation by Issam Awad and Rustam Al-Shahi Salman and a discussion of clinical drug trials. Rustam Al-Shahi Salman helped the researchers to understand the number of participants that would be needed in order to run an approved, effective trial of any medication. The bare minimum number of patients is 1500, but as many as 30,000 may be needed depending on how powerful the medication turns out to be. The Angioma Alliance Patient Registry still has fewer than 400 participants and many are ineligible for medication trials because they no longer have a lesion or are on statins. It is clear that an international effort will be required in order to recruit sufficient participants. It is also clear that, because of our small numbers, we will not be able to test a large number of medications and must choose very carefully the one or two medications that are likeliest to have an impact. This means a longer time spent with animal testing and with other screening methods rather than moving quickly to human trials.

The afternoon presentations were spent exploring different facets of the progress of the University of New Mexico/UCSF/Angioma Alliance joint study. This study has now recruited 100 of the 500 individuals with the Common Hispanic Mutation they intend to recruit – finding patients who are willing to participate is a challenge in this project as well. The study is nearly ready to begin a very small pilot study of a statin medication to see if there is any impact on the leakiness of vessels in humans. As the project continues, the researchers will be tracking study participants for 5 years using MRI and medical records. They will be documenting what they find and comparing the progression of the illness with results of a genetic test called a genome wide association study (GWAS). GWAS may help us to understand what other biological factors may play a role in worsening the illness in some people.

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Scientific Workshop Day 2

Apologies for the delay in this post – the day was quite full yesterday. The Thursday presentations were quite exciting with more talk about medications to treat cavernous angiomas but also discussion of unexpected impacts of CCM mutations. Here is the list of topics and presenters:

“Loss of KRIT1 (ccm1) leads to increased vascular permeability and modifies inflammatory responses in vivo” was presented by Angela Glading of the University of Rochester.

“Defective vascular integrity upon ICAP-1/Krit1 complex loss correlates with aberrant beta 1 integrin-dependent dialog between the endothelial cell and its extracellular matrix” was presented by Eva Faurobert from Grenoble, France.

“Loss of Ccm3 in neuroglia leads to cerebral cavernous malformations and vascular pathology” was presented by Angeliki Louvi of Yale.

These three presentations were continuations of presentations from previous conferences and already published papers. They examined implications of the mutations that were not strictly related to the vascular malformations we all know.

The day’s other presentations touched on medication treatments. They were:

“CCM1 and ICAP1 induce Notch signaling ot inhibit angiogenesis. Animal models and therapeutic implications” by Andreas Fischer of Heidelberg University.

“CCM2 Regulates Superoxide and Nitric Oxide in the Endothelium” by Christopher Gibson of the University of Utah

“Fasudil Decreases Lesion Burden in a Murine Model of Cerebral Cavernous Malformation Disease” by Dave McDonald of Duke University.

While I’m not able to discuss details, I can say that there is, as yet, no perfect medication identified for treating cavernous angiomas. A challenge will be finding an effective medication that is also suitable for long term use. However, I can say that new and better techniques are being developed to evaluate potential compounds.

Some images of the day:

Angela Glading and Andreas Fischer, two of the day’s presenters discussing their work during a break:

Angela Glading and Andreas Fischer

Even though researchers are at the same institution, this doesn’t mean they have opportunity to talk about their work in as much depth as they’d like. Here Blaine Hart, Leslie Morrison and Beth Baca of the University of New Mexico have a rare chance to discuss their data.

University of New Mexico Research Group

After the day’s sessions, groups of scientists went off to enjoy some of the local sights. Here a multi-national group visits the Chateau de Chantilly.  Israel, Italy, and the US are represented.

Scientists at the Chateau de Chantilly

Friday is the last day of the workshop with a full day of sessions on new imaging techniques that allow for better modeling of lesions for research (3-D images and 7 Tesla SWI images are ultra-cool), clinical drug trials, and genetic and clinical studies.


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