Diseases related to thrombus and fibrosis are a key contributor to strokes, heart attacks, organ failure, and death and result in billions of dollars in health care costs each year.
Thrombus—the formation of blot clots—is the most common underlying pathology of ischemic heart disease, myocardial infarction, stroke, and venous thromboembolism.
Fibrosis—the formation of excess connective tissue that thickens and scars as a result of organ injury—is a key driver of a wide range of disorders, such as chronic kidney disease, atrial fibrillation, hypertrophic cardiomyopathy, nonalcoholic steatohepatitis, idiopathic pulmonary fibrosis, inflammatory bowel disease, as well as some cancers. About half of deaths in the developed world are caused by diseases that have a fibro-proliferative component.
New non-invasive imaging modalities developed by Peter Caravan, PhD, an investigator at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital and associate professor of radiology at Harvard Medical School, could help to answer these questions.
The Caravan Lab has developed new radiochemical tracers that bind to proteins that play a key role in each condition. He is now collaborating with Mass General Hospital clinicians to translate them into clinical practice.
Caravan, co-director of the Institute for Innovation in Imaging (i3) at Mass General, also works closely with Partners Innovation to collaborate with industry partners on projects related to target confirmation, testing the efficacy and safety of treatments, clinical trial planning and regulatory filings. The Innovation team has also supported Caravan’s fibrosis research through an Innovation Discovery Grant.
While each project in The Caravan Lab may have different targets, imaging modalities and clinical goals, their development often follows a similar path.
“We start out with an unmet need, then work on the chemistry and start testing things in laboratory models and with different imaging paradigms,” Caravan explains. When something works well in these preclinical studies, the team then works with Mass General clinicians to transfer their findings into the clinic.
“What drew me to Mass General was the ability to do translational research,” he says. “My colleagues on the clinical side have been so supportive. That’s something that cannot be overstated—what can happen at Mass General.”
For fibrosis, the team developed chemical probes that can target type 1 collagen and contain reporters that can make the probe detectable by magnetic resonance imaging (MRI) or positron emission tomography (PET).
“Collagen is the most abundant protein in the body and might not seem like an obvious target because of its potential high background (the large amount of it in the body),” he acknowledges. “But the way we engineered the molecule allowed us to have good specificity for pathological fibrosis. The collagen fibrils there are much less organized than in normal tissue, so you have more surface area for uptake.”
He is now working to assess the safety and efficacy of the probe in both MRI and PET, each of which has its advantages and limitations.
The first clinical study of the PET probe was designed to assess treatment response in patients with idiopathic pulmonary fibrosis (IPF). The team recently published their results in the American Journal of Respiratory and Critical Care Medicine.
This was a first-in-human study in collaboration with Mass General pulmonologist Sydney Montesi, MD, thoracic surgeon Michael Lanuti, MD, and Ciprian Catana, MD, PhD, director of Integrated MR-PET Imaging. “In IPF, there really is a challenge in prognosis,” Caravan says. “We don’t know how the disease is going to progress and what patients will benefit from which therapy.”
For thrombus, Caravan’s imaging probe targets fibrin—a protein that forms when the blood clots but is not present in circulating blood or in the body unless there is a wound healing.
In collaboration with Catana and David Sosnovik, MD, director of the Cardiovascular Research Center at Mass General, he has been testing the probe in patients with atrial fibrillation (AF). AF patients are prone to developing blood clots that put them at high risk of stroke.
The team has now imaged 30-plus subjects and compared the results of their probe against an established—but more invasive—diagnostic test called transesophageal echocardiography.
“In terms of accuracy, it actually looks perfect at the moment,” Caravan says. “There have been no false positives and no false negatives.”
While continuing to test these probes in the clinical setting, Caravan also sees opportunities to collaborate with industry partners.
“In fibrosis, there are needs around patient selection for trials and assessing early response to treatment. In thrombosis, there is potential for assessing safety in cardiovascular indications and to detect clots that form around valve replacements and left ventricular assist devices.
“In drug development, we also want to know early on if the treatment is effective. If you could look at a small cohort and get a sense that something is working, then you would be more likely to bring that forward into phase two clinical trials.”