2015 ExRNA Projects: Therapies

NCATS is administering 18 new NIH Extracellular RNA (exRNA) Communication program projects as a next phase to test and validate exRNA molecules for their potential as disease biomarkers and treatments. Funded by the NIH Common Fund, these projects are aimed at advancing exRNA-based therapies to the point where Investigational New Drug applications can be filed with the Food and Drug Administration to launch human studies.

Exosome-Based Therapeutics in Huntington’s Disease

Investigator: Neil Aronin, M.D., University of Massachusetts Medical School, Worcester
Grant Number: UH2-TR000888

Huntington’s disease is an inherited disorder that causes memory and thinking problems, abnormal movements, and depression. The disease usually starts in adults between the ages of 30 and 40 and worsens throughout a person’s life. People with Huntington’s disease eventually become unable to take care of themselves and often must live in costly nursing facilities. Huntington’s disease is caused by a change, or mutation, in the gene that codes for a protein called huntingtin. The mutation causes the body to make abnormal versions of the huntingtin protein, which damages brain cells and produces symptoms of the disease. In animal models of Huntington’s disease, a type of exRNA called small interfering RNA (siRNA), when injected into the brain, can block production of the abnormal huntingtin protein, reducing symptoms of the disease. However, clinicians must directly inject this substance into the brain, which is not an ideal delivery method in humans. In this project, investigators will inject exosomes — tiny particles produced by most types of cells that can contain and transport exRNA — into the blood of mice with Huntington’s disease. The exosomes will travel through the blood to deliver the therapeutic siRNA to the brain. Eventually, researchers could use these siRNA-containing exosomes to treat humans with Huntington’s disease and to develop treatments for other brain diseases.

Learn more about this project in the NIH RePORTER.

Exosome RNA — Therapeutics to Promote Central Nervous System Myelination

Investigator: Richard P. Kraig, M.D., Ph.D., University of Chicago
Grant Number: UH2-TR000918

Multiple sclerosis (MS) is a disease in which the body’s immune system attacks and destroys the protective covering of the nerves, called the myelin sheath, through a process called demyelination. Over time, the brain, the spinal cord and the rest of the body lose the ability to communicate. Many people with MS eventually lose the ability to walk or speak clearly. MS affects about 2.5 million people worldwide, including 400,000 in the United States. Current MS therapies can slow the disease by reducing demyelination, but no treatment exists to restore the lost myelin, called remyelination. Research has shown that exosomes that contain a type of exRNA called microRNA (miRNA) can trigger remyelination. The investigators plan to develop exosomes containing miRNA as a therapy for brain remyelination and treatment of MS.

Learn more about this project in the NIH RePORTER.

Graphic showing how exRNA molecules released from immune cells can enhance myelination and thus counteract the de-myelinating effects of conditions including aging, migraine and MS.

This figure is a series of illustrations that show how exRNA molecules released from immune cells can enhance myelination and thus counteract the de-myelinating effects of conditions including aging, migraine and MS. A mouse running on a wheel represents environmental enrichment (EE), which triggers immune cells to release exosomes containing microRNA-219 (miR-219) into the bloodstream (depicted by a blood vessel containing circular exosomes in the blood). Similarly, this effect can be mimicked in cultured dendritic cells (depicted by a drawing of a dendritic cell in a petri dish releasing circular exosomes) by stimulating them with interferon gamma. The figure shows that through either method, exosomes containing miR-219 cross the blood-brain barrier and interact with a precursor cell in the brain. In the next part of the figure, these precursors become mature myelinating cells. The figure shows that migraine, aging and MS block this myelinating process. These stimulated dendritic cell exosomes could represent a novel therapeutic for MS, migraine and other neurodegenerative diseases associated with myelin loss. (University of Chicago Photo)

Fruit Exosome-Like Particles for Therapeutic Delivery of Extracellular miRNAs

Investigators: Huang-Ge Zhang, M.D., D.V.M., Ph.D., University of Louisville, Kentucky, and Peixuan Guo, Ph.D., University of Kentucky, Lexington
Grant Number: UH2-TR000875

Exosomes from mammals can deliver drugs for chemotherapy. This method is not ideal because it is hard to produce the large numbers of exosomes needed and because a patient’s immune system could reject the exosomes. Researchers can, however, remove large amounts of edible exosome-like particles from grapes. These exosomes can transport chemotherapy drugs. Scientists can alter the exosomes so that they can travel to the brain and, when given orally, to the liver. This research team will determine whether these exosomes can deliver therapeutic miRNA to cancerous cells of the colon, breast and brain. The team also will determine whether it is possible to produce large amounts of exosomes inexpensively for use in the clinic. The scientists hope to create a therapeutic delivery system that can be used more widely both for research and for treatment.

Learn more about this project in the NIH RePORTER.

Left: Huang-Ge Zhang in a laboratory holding a dish of red grapes. Right: microscopic image of exosome-like particles from grapes.

A research team led by Huang-Ge Zhang, Ph.D., at the University of Louisville has shown that large amounts of exosome-like particles from grapes and other edible plants can deliver therapeutic miRNA and chemotherapy drugs for potential treatment of cancer. Zhang is shown on the left in a laboratory holding a dish of red grapes; on the right is a microscopic image of exosome-like particles from grapes. (University of Louisville Photo)

HER2-Targeted Exosomal Delivery of Therapeutic mRNA for Enzyme Pro-Drug Therapy

Investigator: A.C. Matin, Ph.D., Stanford University, California
Grant Number: UH2-TR000902

HER2-positive breast cancer is an aggressive type of breast cancer that responds poorly to treatment because the cancer cells produce a protein that promotes tumor growth. The investigators plan to enhance the natural ability of exosomes to transport molecules by attaching them to a new drug that targets and kills HER2-positive breast cancer cells. The drug also becomes fluorescent when it attacks the cancer cells, so researchers can see it within a living animal. The research team will load exosomes with this drug and test it in animals. The team aims to develop a more effective treatment for aggressive HER2-positive breast cancer and improve outcomes for patients with this disease.

Learn more about this project in the NIH RePORTER.

Novel Extracellular RNA-Based Combinatorial RNA Inhibition Therapy

Investigators: Anil K. Sood, M.D., George A. Calin, M.D., Ph.D., and Gabriel Lopez-Berestein, M.D., University of Texas M.D. Anderson Cancer Center, Houston
Grant Number: UH2-TR000943

Ovarian cancer is the most deadly cancer of the female reproductive system. Because women usually have mild or no symptoms during the cancer’s early stages, it is often not diagnosed until it has spread to other organs in the body. By the time the cancer is advanced, treatments are effective only for short periods. One type of miRNA can enter ovarian cancer cells and enhance their growth. The investigators will develop a new treatment approach that removes this cancer-promoting miRNA from human tumor cells and blocks additional miRNA from entering them. Researchers could add this method to current ovarian cancer treatments to enhance their effects. The methods developed will apply to the treatment of many cancers.

Learn more about this project in the NIH RePORTER.

Regulation of Renal and Bone Marrow Injury by Extracellular Vesicle Non-Coding RNA

Investigator: Peter J. Quesenberry, M.D., Rhode Island Hospital, Providence
Grant Number: UH2-TR000880

Microvesicles are tiny particles that contain exRNA, are produced by most types of cells, and can contain and transport various types of exRNA through the body. Microvesicles from stem cells can heal injured kidney and bone marrow tissue by delivering a therapeutic type of exRNA called non-coding RNA. For this project, investigators will search for non-coding RNA in microvesicles from stem cells that can heal injured kidney and bone marrow stem cells. The investigators then will develop a way to deliver the non-coding RNA to help injured kidney or bone marrow tissue regrow. This study could lead to the development of non-coding RNA therapy for bone marrow diseases and kidney damage in humans.

Learn more about this project in the NIH RePORTER.

Targeted Delivery of MicroRNA-Loaded Microvesicle for Cancer Therapy

Investigators: Thomas D. Schmittgen, Ph.D., and Mitch A. Phelps, Ph.D., The Ohio State University, Columbus
Grant Number: UH2-TR000914

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third deadliest cancer, causing 1 in 10 cancer deaths worldwide. No effective therapy exists, and patients with advanced HCC ultimately die from the disease. Certain types of miRNA can block HCC tumor cell growth and represent a potential treatment for this deadly disease. However, miRNA is expensive to develop, degrades rapidly and is potentially toxic to healthy tissues, so development of miRNA-based therapies has been challenging. To address these problems, the investigators will develop naturally produced miRNA and package it into microvesicles that protect the miRNA and direct it to HCC tumors. The research team will program cells grown in the laboratory to produce the miRNA-loaded microvesicles. Then they will remove the microvesicles from the cells and test them in animals with HCC. Eventually, these microvesicles could be tested in HCC patients. This technology also could be used in the future to deliver other types of RNA drugs for a variety of other cancers and diseases.

Learn more about this project in the NIH RePORTER.

Targeting Tumor-Derived ExRNA-Containing Microvesicles by High-Throughput Screening

Investigator: Asim Abdel-Mageed, D.V.M., M.S., Ph.D., Tulane University School of Medicine, New Orleans
Grant Number: UH2-TR000928

Castration-resistant prostate cancer (CRPC) is cancer of the prostate gland that continues to grow despite treatments that stop the body from using testosterone, a hormone that some tumors rely on for growth. Unraveling the biology of tumor growth and spread is critical to developing treatments for CRPC. Recent findings show that certain types of exRNA released by CRPC tumors appear to cause further tumor growth. This exRNA is contained in microvesicles. Drugs that target and destroy these microvesicles could slow or stop tumor growth. This project will test thousands of already approved drugs for the ability to block the activity of microvesicles and slow the growth of tumors in cell cultures and animals. Testing already approved drugs reduces the time and high cost of drug development, allowing promising drug candidates to be used in patients sooner.

Learn more about this project in the NIH RePORTER.