Based on our inside knowledge of the CCM field and our understanding of the greater research landscape, the Alliance to Cure Cavernous Malformation looks for high-impact, generally high-risk/high-reward opportunities for funding. We search for potential research partners, focusing our outreach on programs with the best potential to move the work forward. Once we have selected a partner and they have accepted, we collaborate on the research plan and budget. At this time, we do not accept unsolicited grant applications.
CURRENTLY FUNDED PROJECTS
CureDriver™ Lab: Alliance to Cure Preclinical Testing
Many potential treatments for CCM have not been tested in models of CCM disease. These medicines are already on the market or in development for other illnesses and have biological justification to be tested for CCM.
Unfortunately, there is nowhere to do this. Academic labs are busy with their NIH-funded projects that will lead to publications. Pharmaceutical companies will not develop the infrastructure of CCM pre-clinical models – cell lines and animal models – to test just one drug. So, many potential treatments are waiting on shelves instead of moving toward patients.
To address this, the Alliance to Cure has taken the ground-breaking step of creating a pre-clinical treatment testing program, our CureDriver™ Lab. To start, we are testing more than a dozen compounds, alone and in combination, in various models of CCM disease. Initial cell-line testing is happening in academic labs; promising compounds will receive in-depth animal model testing under our direction in our mouse colony at a contracted scientific research organization (SRO). If any drug effectively slows or stops CCM in the lab, it will become a candidate for our industry and academic partners to test in clinical trials. This is our biggest investment – depending on the number of drug candidates we test, we expect an annual cost of $200,000-$300,000.
Dr. Amy Akers, our Chief Scientific Officer, leads the project. Dr. Akers has been engaged in CCM research since 2005, first as a graduate student in the Duke University laboratory of Dr. Doug Marchuk, our current Scientific Advisory Board Chair, and from 2009, as our Chief Scientific Officer. In Dr. Marchuk’s lab, Dr. Akers performed experiments that confirmed that some sporadic CCM lesions have the same mutations as familial lesions, with the mutations localized to the lesion. With the Alliance, Dr. Akers serves as the liaison to and consultant for the global scientific community, has been responsible for developing our biobank, and is the project manager for our Clinical Care Consensus Guidelines. She is a co-author of 17 CCM research papers. Her role as lead for this treatment-testing project is a natural next step.
Targeted Drug Delivery Using Nanoparticles
With the help of a generous major donor, we are funding the exploration of advanced drug delivery methods to get treatments directly to lesions. This work goes hand-in-hand with the recent discoveries of the benign tumor-like biology of CCM and some preclinical and clinical evidence of the effectiveness of various cancer drugs in treating CCM and other blood vessel overgrowth diseases. If we need to resort to cancer drugs to treat CCM, we want to target the drugs’ activity mainly to the lesion itself to prevent side effects. Targeted drug delivery research and implementation are already well underway in other diseases. It’s time for us to figure out how to make it work for CCM. In April 2024, the Alliance to Cure Cavernous Malformation funded $75,000 to the laboratories of Drs Jan-Karl Burkhardt, M.D., and Mark Kahn, M.D., Ph.D. The funding will be used for developing and preclinical testing of brain endothelial-targeted blockade of PI3K-mTOR signaling as a treatment of CCM.
Developing an AAV-based targeting vector specific for brain endothelial cells
Although finding a treatment for CCM is essential, gene therapy might be a way to functionally cure it. The Alliance to Cure Cavernous Malformation has awarded $18,400 to Dr. Angela Glading at the University of Rochester to develop a brain endothelial cell-targeting AAV-based vector to deliver a wild-type copy of a CCM gene specifically to brain vessels. Once it’s developed, this would make gene therapy a safer option for CCM patients. Our funding will cover a small but critical portion of this work.
PAST FUNDED PROJECTS
Focused Ultrasound
The Alliance to Cure Cavernous Malformation awarded $87,000 to the laboratory of Dr. Petr Tvrdik at the University of Virginia to fund research using focused ultrasound and sonosensitizers as a treatment for CCM. Focused ultrasound has several mechanisms of action. Like laser surgery, it can work through ablation by heating and destroying tissue. It can also be used with a substance that becomes caustic when exposed to focused ultrasound. This is called sonodynamic therapy and requires a minimal increase in temperature. The initial work is being conducted in cultured human cells and mouse models of CCM.
CD5-2
In 2020, the Gamble lab at the University of Sydney’s Centenary Institute published targeting miR-27a/VE-cadherin interactions rescues CCM in mice in which they explored the use of CD5-2, a target site blocker that prevents the mRNA interaction of miR-27a/VE-cadherin in mice bred with CCM mutations. CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. There were two limitations to this experiment – the experimental mice were very young and didn’t have established lesions when the treatment began. Additionally, individual lesions were not monitored over time. This is because Centenary did not have mouse models that survived into adulthood and did not have the technology for mouse MRI. In 2023, the Alliance to Cure Cavernous Malformation funded the next step in this research – testing CD5-2 in adult mice with established lesions and following the progression of these lesions over time using MRI. To our knowledge, this is the first time sequential MRI was used to see treatment effects in a mouse model.
Updated 8/20/2024
