A new experimental drug offers protection against sudden death.
TOPICS:BloodDrugsNanoparticlesSouth Florida University St. Louis’ Washington University
The drug could pave the way for treatments for people who are at risk of abdominal aortic aneurysm rupture.
According to a study conducted by scientists at Washington University School of Medicine in St. Louis, an experimental drug therapy protects mice from sudden death caused by the rupture of a major blood vessel in the abdomen.
The findings, published in the journal Biomaterials Advances, may pave the way for a new approach to treating abdominal aortic aneurysms, a condition in which the wall of the abdominal aorta, a major blood vessel that transports blood from the heart to the rest of the body, weakens and bulges outward. Without warning, the weak spot can begin to leak blood or burst, resulting in a serious emergency that, if not treated promptly, almost always results in death. The larger the aneurysm, the more likely it will rupture unexpectedly.
“We monitor people who have a medium or small aneurysm,” said senior author Christine T. N. Pham, MD, the Guy and Ella Mae Magness Professor of Medicine and Director of the Division of Rheumatology. “While large aneurysms can be repaired surgically, there is no treatment for smaller aneurysms other than waiting for them to grow to a size that can be repaired surgically.” Our findings in mice suggest a potentially useful therapy that could prevent aneurysm rupture.”
In St. Louis, Pham sees patients at Barnes-Jewish Hospital and the Veterans Affairs Medical Center.
Every year, approximately 200,000 people in the United States are diagnosed with abdominal aortic aneurysm, also known as triple A, with the majority of them being older male smokers. Such aneurysms frequently show no symptoms until they rupture suddenly and catastrophically, killing 15,000 people in the United States alone each year. According to the U.S. Preventive Services Task Force, a group of independent experts in disease prevention and evidence-based medicine supported by the U.S. Department of Health and Human Services, all men aged 65 to 75 who have ever smoked should get ultrasound scans to test for triple A.
Scientists have known for decades that triple A is caused by inflammation in blood vessels, but efforts to treat the disease with immunosuppressive therapies have failed. The immune system is an important part of the body’s infection defences. It is difficult to strike a careful balance between reducing aorta inflammation sufficiently to prevent aneurysms from worsening and suppressing the immune system in the rest of the body to the point where a person becomes susceptible to severe infections.
The researchers used nanoparticles to deliver anti-inflammatory payloads directly to inflamed blood vessels in this study. The nanoparticle is based on a melittin protein fragment that has been optimised to carry the payload: small bits of RNA. When given to mice, the modified protein fragment forms a complex with RNA and accumulates primarily in inflamed tissues. The protein fragment unloads the RNA and aids its entry into the cell’s main compartment, where it suppresses inflammation by interfering with the expression of an important inflammatory protein, NF-kappaB.
The basic version of the nanoparticle was created at Washington University School of Medicine by co-author Samuel A. Wickline, MD, who is now a professor at the University of South Florida and the chief scientific officer at the biotechnology company Altamira Therapeutics. The nanoparticle used in this study was optimised by Wickline, Pham, and their Washington University co-authors Hua Pan, Ph.D., an associate professor of medicine, and first author Huimin Yan, MD, Ph.D., a staff scientist.
The nanoparticles were used to deliver small interfering RNAs (siRNAs) that targeted two NF-kappaB subunits: p50 and p65. The researchers looked at male mice who developed a triple A-like condition that ruptured roughly half of the time. For comparison, they gave the mice nanoparticles containing p50 siRNA, p65 siRNA, or an irrelevant siRNA. Suppressing p50 did not stop the aneurysms from growing, but it did increase the mice’s chances of survival from 53% to 85%. The treatment also postponed the onset of rupture from day seven to day twelve. Suppressing p65, on the other hand, had no discernible effect.
“By optimising the nanoparticle, we were able to use a fraction of the previously established dose of siRNA, which means we can achieve a therapeutic effect at a lower risk of adverse effects,” Pan explained. “By targeting p50 and p65 separately, we were able to piece together the individual contributions of the different subunits and identified one (p50) that we believe will be more protective with fewer potential side effects.” Overall, these findings are very encouraging. They imply that developing a therapy to reduce the risk of rupture and death from triple A without unacceptable side effects may be feasible.”
Wickline is the principal investigator and Pham is the Washington University site lead on a National Institutes of Health (NIH) Small Business Technology Transfer grant involving the original nanoparticle technology developed by Wickline and his team at Washington University. In collaboration with Altamira Therapeutics, the grant funds a project to develop and commercialise the technology as a treatment for inflammatory disease.
“For that grant, we’re looking at rheumatoid arthritis rather than triple A,” Pham explained. “However, once a technology is approved for one disease, it is much easier to apply it to other diseases.” I’m hoping that one day, in the not-too-distant future, we’ll be able to offer people a treatment to stabilise the aneurysm, reducing the risk of rupture and sudden death. Although the technology is still being tested, there is more hope now.”
Huimin Yan, Ying Hua, Antonina Akk, Samuel A. Wickline, Hua Pan, and Christine T.N. Pham, “Peptide-siRNA nanoparticles targeting NF-B p50 mitigate experimental abdominal aortic aneurysm progression and rupture,” Biomaterials Advances, 6 July 2022.
The National Institutes of Health and the Department of Veterans Affairs funded the research.