MIT researchers have developed an engineered liver tissue model that can be manipulated with RNA interference.Credit: MIT/Liliana Mancio-Silva
An engineered model of human liver tissue can be used to investigate the effects of RNA interference (RNAi), helping to accelerate the development of RNAi-based treatments, according to MIT researchers. Their work was published this week in the journal Cell Metabolism.
The researchers showed with the model that they could use RNAi to turn off a gene that causes a rare hereditary disorder. And using RNA molecules that target a different gene expressed by human liver cells, they were able to reduce malaria infections in the model’s cells.
“We showed that you could look at how this new class of nucleic acid therapies, especially RNAi, could affect rare genetic diseases and infectious diseases,” said Sangeeta Bhatia, senior author of the study.
Bhatia is the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science. She is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.
The authors noted that the liver tissue model can also be used to manipulate metabolic enzyme levels, which could help to predict how different patients would metabolize drugs, allowing researchers to identify possible side effects earlier in the drug development process.
MIT research scientist Liliana Mancio-Silva is the lead author of the paper. Other authors include Heather Fleming, director of research for Bhatia’s lab; Alex Miller, an MIT graduate student; and Stuart Milstein, Abigail Liebow, Patrick Haslett, and Laura Sepp-Lorenzino of Alnylam Pharmaceuticals.
Human liver tissue is difficult to grow outside of the human body, the authors said. Several years ago, Bhatia and her colleagues first demonstrated they could grow human hepatocytes, the main type of liver cell, on special micropatterned surfaces, surrounded by supportive cells. This architecture creates a microenvironment in which human liver cells function in much the same way as they do in humans.
The team has since used the model to test small-molecule drugs for diseases like malaria. For their latest study, the researchers wanted to demonstrate the model's usefulness for testing the delivery of nucleic acids such as RNA. They explained that through RNAi, short strands of RNA can be used to block the expression of specific disease-causing genes.
The researchers modeled alpha-1 antitrypsin-associated liver disease, a rare genetic disorder that causes the alpha-1 antitrypsin protein to misfold and accumulate in hepatocytes. They found that the RNA they delivered to the cells of the liver model could reduce the expression of the protein by about 95%. Dozens of other disorders of the liver could benefit from genetic manipulation, Bhatia said.
The researchers also tested an RNAi treatment designed to treat infectious diseases by turning down genes expressed by the host, which the pathogen normally exploits to infect the host. In this case, they delivered RNA that interferes with a gene that encodes a cell surface receptor that the malaria parasite requires to get into liver cells and infect them.
Other host genes could be targeted to treat infectious diseases such as hepatitis B. In some patient settings, Bhatia said, this kind of treatment could be preferable to having patients take daily pills over a long period of time because a single shot of RNA has been shown to turn down gene expression for several weeks.
The study also showed that the model could be used to test the possible side effects of traditional small-molecule drugs. The liver is responsible for metabolizing such drugs, and liver damage from these drugs is one of the biggest reasons that clinical trials fail, the researchers noted.
New drugs have to be tested under different conditions because different people can express varying levels of the metabolic enzymes used to break down drugs. Usually, this is done in human liver tissue treated with drugs that inhibit certain metabolic enzymes, but these drugs are not highly specific and can block multiple metabolic pathways at once.
The MIT researchers used RNAi to reduce levels of two metabolic enzymes that belong to a family known as cytochromes P450. They were then able to test how the liver cells metabolized acetaminophen (Tylenol) and atorvastatin (Lipitor), which can damage the liver in some cases. They showed that the tissue model accurately replicated how these drugs are broken down when varying levels of metabolic enzymes are present.
Bhatia said this kind of drug screening could make it easier for researchers to test the potential responses of many different types of people, using cells from just one donor, manipulated with RNAi.
It's possible that this model could also be used to study gene therapy, which the researchers plan to explore in future studies.
The research was funded by the Bill and Melinda Gates Foundation, Alnylam Pharmaceuticals, and the Koch Institute Support (core) Grant from the National Cancer Institute.