Repurposing Propranolol as Potential Therapy for CCM
The goal of [Dr. Doug Marchuk’s] research lab [at Duke University School of Medicine] is to understand the underlying mechanisms of CCM formation, to use this knowledge to generate a mouse model of the disease that faithfully copies the features seen in the human disease, and finally, to test existing and/or new drugs in our animal model to identify a drug that will reduce CCM lesion burden and bleeding.
Mice and humans are both mammals, but mice can be genetically manipulated and yet are not as expensive to maintain as other mammals, so the laboratory mouse has become the species of choice for many pre-clinical (meaning occurring before the drug is ever given to a patient) drug studies. These animal/mouse studies are crucial to pave the way for eventual clinical trials in human patients. Animal studies provide a reproducible way to efficiently test a drug without the concern of doing harm to the patients or without long-term, costly (in terms of money and labor) treatment of patients that may or may not prove effective. Only those drugs that pass the test of safety and medical effectiveness in animals are likely to move forward into a clinical trial in patients. And only a controlled clinical trial can convince the medical community that a drug actually is an effective treatment for disease.
A major problem with a mouse model of any disease is that these often do not fully copy the important features of the human disease. Over the past decade we have generated a series of mouse models of CCM disease that with each successive iteration, more closely resemble the medically important features of the human CCM disease. We are continuing to improve the mouse models by “tweaking” the way we generate the animals. One of the key features of a good mouse model of CCM is whether the CCM lesion will bleed/hemorrhage, since this is the feature for the CCM disease that causes the most serious medical problems.
Drug “repurposing” is the idea of using an existing drug currently approved for one disease/indication for use in a new, different disease. This approach is widely used because most or all of the drug safety issues have already been resolved, so IF the drug is effective in the new disease/indication, the path forward into patients is already open and clear. Dr. Zabramski and others have recently suggested propranolol as a potential therapy for CCM. Propranolol is currently used to treat infantile hemangiomas, a different vascular malformation, so using propranolol for CCM would be an example of drug repurposing. Dr. Zabramski has treated a few CCM patients with propranolol that appear to have improved due to the treatment. Unfortunately, this sparse human data alone is insufficient to motivate a large clinical trial to test the medical use of propranolol. So the goal of this mouse study is to formally test propranolol in our newest mouse model(s) of CCM disease. We are currently treating two different models of CCM with propranolol to determine if it will decrease the size and/or number of CCMs (so called “lesion burden”) and in a slightly different mouse model, determine if the drug will decrease bleeding from the CCMs.