Stopping the Stops: A Novel Therapeutic Approach for Hemorrhage from Vascular Malformations
Abstract
Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area: Vascular Malformations. Hereditary Hemorrhagic Telangiectasia (HHT) is an inherited condition that causes vascular malformations to form in the nose and internal organs, such as the lungs, liver, and brain. The abnormal blood vessels are prone to severe bleeding that can be life-threatening, or result in life-changing events such as stroke. Two-thirds of people with HHT have nosebleeds more than once a week. When it becomes impossible for diet to replace the iron losses, these people become chronically anemic, tired, dependent on iron treatments and blood transfusions, and therefore exposed to even more complications. Currently there are few effective treatments for HHT. Between 40,000 and 60,000 people are thought to be affected in the United States, though most are not diagnosed and do not know why people in their family have nosebleeds, early strokes, and/or deaths. On average, individuals with HHT pass on HHT to half of their children. This is because they have a mistake in their DNA that codes for signaling molecules in blood vessel cells. Gene changes (mutations) have been identified in three different genes, all of which disrupt the same signaling pathway that is important for blood vessels to develop properly. Our hypothesis is that if we can correct the abnormal cell signaling that results from these DNA changes, we may be able to reduce the amount of bleeding, improving survival and quality of life. Since the gene mutations were identified (and for one of the HHT genes, this was more than 20 years ago), no molecular-based therapies have been developed, as it has been very difficult to see how the signaling problem could be corrected while the DNA was still giving the wrong message. A new group of molecular therapies provide a novel opportunity to actually correct the message from mutated HHT genes. In this study, we will take the first steps towards that goal, and test two different drugs using cells from patients with HHT. The two drugs, ataluren and amlexanox, work by enabling cells to bypass a particular type of DNA gene change known as a nonsense mutation. These mutations produce a "stop" signal that occurs too early in the message from the gene and prevents the cell from making the correct protein. One in five DNA changes that cause HHT are nonsense mutations. By "stopping the stops" and changing them back to "go," these drugs should allow HHT cells to start making the correct protein again, at the right time and in the right place. It is then not necessary to fully understand when the proteins need to be made; the drugs would allow the cell to decide. Both drugs have been used in humans before, but not in HHT. Ataluren is an investigational drug already in clinical trials for two genetic diseases, while amlexanox is an anti-inflammatory drug that was only recently found to have the ability to stop nonsense mutations. In the proposed study, we will test these drugs in 15 different HHT mutations and perform experiments to understand why some mutations respond well to the drugs whereas others do not. People with HHT will be recruited at Imperial College London, a specialist HHT center that sees about 200 new patients each year. Blood samples from these participants will be used in two ways. Endothelial cells, which line the blood vessels and are abnormal in HHT, will be isolated and used to study whether the drugs can correct the signaling problems that cause HHT. However, it takes at least 4 weeks to grow enough cells for these studies, so we will also test if the same results can be obtained more quickly using blood cells immediately after the sample is collected. It is likely that some mutations will respond better to these drugs than others, but currently there is no way to predict this. The goal of this study is to test different types of mutations in the three HHT genes in order to try and predict which pati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610607
Entities
People
- Micheala Aldred
Organizations
- Cleveland Clinic
- United States Army