Cerebrovascular research advances clinical care at Penn Medicine
Physician-scientists at Penn Medicine are conducting clinical trials to better understand cerebrovascular disease and identify treatment targets.
Aneurysms, cavernous malformations, and other cerebrovascular diseases (CVDs) are a leading cause of death and disability worldwide. These conditions can have severe consequences—including stroke, seizures, paralysis, functional and cognitive deficits, and hearing and vision loss—that affect lifespan and quality of life. Research is essential to the development of better strategies for CVD prevention, diagnosis, and treatment.
Physician-scientists in Penn Medicine’s cerebrovascular surgery program offer advanced care for these conditions and conduct exciting basic research and clinical trials to continually move the field forward.
“We’re very much involved in developing the next generation of treatments for cerebrovascular conditions,” says Visish Mani Srinivasan, MD, a Penn Medicine cerebrovascular neurosurgeon. “One of our goals is to translate new technologies into use in our patients. This includes using new devices that have been made elsewhere, as well as some novel things we’re working on in our own research labs. Being able to bring those advances to actual clinical treatments is one of the most exciting parts of our work.”
Jan-Karl Burkhardt, MD, division head of Penn Medicine Cerebrovascular Surgery, explains that Penn Medicine is uniquely poised to conduct this type of work. “Our research advances are possible because of a very high volume of patients, advanced diagnostic capabilities, and dedicated research labs,” he says. “This capacity allows us to conduct research to improve outcomes for our patients with conditions such as aneurysms and cavernous malformations.”
Early translation and better understanding of aneurysms
Dr. Srinivasan’s research focuses on better understanding aneurysms, particularly how aneurysms and arteries heal after treatment. “I focus on endothelialization, when a new lining develops on the inside of blood vessels, to better understand how the body returns to normal after the aneurysm is treated,” he says.
In his lab, researchers create aneurysms in a rabbit model by exposing the carotid artery and soaking a small segment with elastase, an enzyme that breaks down the elastic layer of the artery. This restricts the artery’s ability to stretch and recoil with each heartbeat and causes it to bulge. Dr. Srinivasan then treats the formed aneurysm in the same way he would treat it in a human. A month later, he cuts out the aneurysm and studies it, with a focus on endothelialization and gene expression to gain a better biological understanding of aneurysms.
Novel medication for cavernous malformation
The Penn Medicine Cavernous Malformation Center was recently the top enroller in a study of REC-994, an orally bioavailable, superoxide scavenger small molecule that shows promise in the treatment of symptomatic cavernous malformations.
The trial was halted early and found that 50 percent of patients on the 400 milligram dose achieved a reduction in mean lesion volume after 12 months of treatment. Patients also had improved functional outcomes, as measured by the modified Rankin scale. The study found that the treatment was safe, with an incidence of adverse events comparable between treatment and placebo arms, and no treatment-related discontinuations or grade 3 adverse events.
REC-994 now has orphan drug designation for symptomatic cavernous malformations in the United States and Europe. Dr. Burkhardt, a leader in cavernous malformation research, and his colleagues have presented their results at national and international meetings.
Finding pathways to target in cavernous malformations
Dr. Burkhardt and his team also conduct basic research to elucidate the biological underpinnings of cavernous malformations, which could identify treatment targets.
“We have a mouse model where we create exact replicas of these lesions, and that allows us to understand the disease better and look for alternative therapies, including medical therapies to stop or slow their growth,” he explains.
About half of patients with cavernous malformations have a genetic mutation that causes a familial type of the condition. Dr. Burkhardt and colleagues are examining the role of CCM 1, 2, and 3 pathways (proteins encoded by the cerebral cavernous malformation genes) and drugs that might target those mutations.
Penn Medicine researchers are also examining a novel approach with pi3 kinase mTOR signaling pathway. “This pathway is involved in the more aggressive clinical form, when lesions grow faster or bleed. We are working to find medications to block mTOR signaling, especially medications that are already approved for use in other conditions, such as rapamycin,” he says. “We’ve been able to show in a preclinical model that it regresses the growth of the lesions.”
The team is in the process of planning a clinical trial of rapamycin. “The ultimate goal is to translate this into clinical trials so we can use it as quickly and as safely as possible in clinical practice,” Dr. Burkhardt says. “We’re trying to find non-invasive treatment modalities for our patients so that we don’t have to rely on surgery alone.”
Referrals and consultations
To get a second opinion or consultation from a Penn Medicine cerebrovascular surgeon, or to make an emergency transfer, please call 877-937-7366 or refer a patient online.