The grants are funded by the collaborative Extracellular RNA Communication program, supported by the National Institutes of Health Common Fund and led by a trans-NIH team that includes the National Center for Advancing Translational Sciences; National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; and National Institute of Neurological Disorders and Stroke. Only researchers from institutions that have NIH Clinical and Translational Science Awards were eligible to apply for these newly available funds.
The program awarded $17 million for 24 research projects designed to improve scientists’ understanding of a newly discovered type of cell-to-cell communication based on extracellular (outside the cell) RNA, also called exRNA. Through these awards, scientists will explore basic exRNA biology and develop tools and technologies that apply new knowledge about exRNA to the research, diagnosis and treatment of diseases. To unlock the potential of this new scientific field, the awarded research projects will address conditions in which exRNA could play a role, including many types of cancer, bone marrow disorders, heart disease, Alzheimer’s disease and multiple sclerosis.
“We have a tremendous opportunity to explore a recently discovered novel way that cells communicate,” said NIH Director Francis S. Collins, MD, PhD. “Expanding our understanding of this emerging scientific field could help us determine the role extracellular RNA plays in health and disease, and unlocking its mysteries may provide our nation’s scientists with new tools to better diagnose and treat a wide range of diseases.”
“UMass Medical School has been at the forefront of RNA biology for decades. The emerging body of knowledge about the role of small RNAs in cell-to-cell communication in humans has driven home the central importance of regulatory RNAs in human health and disease,” said Terence R. Flotte, MD, the Celia and Isaac Haidak Professor of Medicine, executive deputy chancellor, provost, dean of the School of Medicine and professor of pediatrics. “The National Center for Advancing Translational Science has recognized the tremendous potential of UMMS scientists in this field by awarding Drs. Aronin and Freedman two of these 24 grant awards.”
Scientists think exRNA can regulate many functions in the body and may have an important role in a variety of diseases, but they still know very little about basic exRNA biology. Until recently, scientists believed RNA worked mostly inside the cell that produced it. Now, recent findings show cells can release RNA in the form of exRNA to travel through body fluids and affect other cells. ExRNA can act as a signaling molecule, communicating with other cells and carrying information from cell to cell throughout the body.
Researchers hope to use some kinds of exRNA as biomarkers, or indicators of the presence, absence or stage of a disease. These biomarkers may enable scientists to understand and diagnose diseases earlier and more effectively. Scientists also will use exRNA to develop molecular treatments for diseases.
Dr. Aronin, who is professor of medicine, cell & developmental biology and microbiology & physiological systems, is exploring exosome-based therapeutics in Huntington’s disease.
“Our grant focuses on delivery of small RNAs that can silence the mutant huntingtin mRNA. Huntington’s disease causes neurodegeneration in specific brain regions initially,” said Aronin. “Patients start experiencing symptoms and signs between 30 and 40 years of age—memory loss, depression and abnormal movements. Often, patients require intensive nursing after a few years of disease and do not live beyond 60 years, but quality of life in the last 10 years or more is poor. The disease is inherited as autosomal dominant; this means that a child has a 50:50 chance of inheriting the disease from an affected parent.”
“We have found that RNA interference can silence the mutant gene and, in animal studies, can delay or prevent the onset of disease. However, delivery of the therapeutic small RNAs is a hurdle. The current NIH grant is geared to delivery of therapeutic small RNAs in exosomes. These are small particles found in cells that normally leave the cells to be taken up by other cells. We will make exosomes that take up small RNAs, can be injected into the circulation, cross the blood brain barrier and enter neurons in the brain,” said Aronin.
NIH sponsors the research as part of its Translational Medicine effort and Aronin’s project involves a team of scientists, including Anastasia Khvorova, PhD, professor of molecular medicine, and Phillip Zamore, PhD, Howard Hughes Medical Institute Investigator, the Gretchen Stone Cook Chair of Biomedical Sciences and professor of biochemistry & molecular pharmacology, who along with Aronin are members of the UMMS RNA Therapeutics Institute and the Neurotherapeutics Institute. The project team also includes Marian DiFiglia, MD, PhD, of Mass General Hospital, and Matthew Wood, DPhil, of Oxford University.
Dr. Freedman, who is professor of medicine, is exploring biomarkers for cardiovascular disease using extracellular RNAs.
“Cardiovascular disease (CVD) is the leading cause of death in the United States. Heart disease and stroke, the most common forms of CVD, have common risk factors, including high blood pressure, diabetes, obesity, cigarette smoking and high cholesterol,” explained Freedman. “Certain types of exRNA in the blood affect development and progression of CVD. Researchers have found connections between some of this exRNA and specific forms of CVD. The amounts and types of exRNA may change over time or due to the presence of certain CVD risk factors. Different types of this exRNA could be useful as biomarkers to predict CVD events. To test this possibility, the project team will use blood samples to look for links between exRNA and the presence of CVD. The investigators ultimately will attempt to develop a quick and effective blood test for CVD and its risk factors, using exRNA as a biomarker.”
“NCATS/NIH funding is vital to my research because it bridges my laboratories ongoing basic and clinical sciences. It allows us to translate what we have learned at the bench into understanding large human populations and applying this information to diagnosing and treating disease,” said Freedman, who is also a faculty affiliate in the UMMS RNA Therapeutics Institute. The project team includes Victor Ambros, PhD, the Silverman Chair in Natural Sciences, professor of molecular medicine and a member of the UMMS RNA Therapeutics Institute and the Neurotherapeutics Institute, and Kahraman Tanriverdi, PhD, research assistant professor of medicine, as well as Dan Levy, MD, director of the Framingham Heart Study.
To learn more about the research projects, visit http://commonfund.nih.gov/exrna/fundedresearch.