Researchers have found a way to deliver genes to activating molecules called transcription factors in specific tissues of a live animal for the first time. The approach that many have written off as too difficult technically prevented form of liver damage in mice, although it has many more technical hurdles before it can be used in other tissues, or in people.
"This is a very exciting job," said Hsiang-Rong Tseng, a chemist at the University of California (UC), Los Angeles. ". It will bring the area of provision of transcription factor in a different place "
Our cells produce over a thousand unique transcription factors, each of which binds to a specific region of DNA to ask the transcription of a gene. created from DNA from an RNA template for a new protein Modification of the activity of these factors could, for example, an amplifier for the production of proteins that suppress tumors or reduce inflammation, and even reprogramming of adult cells in immature cells or types of cells. and unlike other gene therapy approaches that introduce permanently DNA to stimulate the production of proteins, factors transcription decompose and leave no lasting effect on the genome.
But cells have ways to close on or destroy relatively large proteins such as transcription factors when they are delivered to the outside rather than to be realized within the cell, said Niren Murthy, a Bioengineering at UC Berkeley. If a transcription factor enters a cell at all, he will eventually digested in a waste disposal organelle called the lysosome, and never will where it can turn on a core gene. "This remains a major unsolved problem," he said. And from proteins, transcription factors are particularly sensitive to chemical modification, he adds. Linking to useful molecules that might interact with cell receptors or penetrating membranes often means changing their chemical structures so they are no longer their work.
in 2011, the group Tseng has found a new way to deliver bulky transcription factors in cells without substantially altering their structure chemical. by setting a transcription factor to a DNA loop that contains the same sequence, it is intended to recognize in the cell, and then wrapping it in a positively charged nanoparticle that can penetrate the cell membrane, they were able to provide the protein in human cells in a dish.
in the new study, Murthy and his colleagues built on this basic concept connection to attach a transcription factor to a part of the DNA, but they used DNA as scaffolding to hold several other molecules that come in handy on the trip of the transcription factor. This new complex, which they called an assembled DNA recombinant transcription factor (DART) has two chemical chains that can disrupt the membrane of a cell lysosome. They are capped with sugar molecules that prevent them from working until the DART is trapped in the highly acidic contents of the organelle. These sugars also originally intended DART specifically the liver cells by interacting with receptors on their surfaces.
For the first prototype DART, the group chose a well-studied transcription factor called Nrf2, which regulates a number of inflammatory and antioxidant genes. "In animal models, it has literally been able to protect against all known inflammatory diseases, from Alzheimer's disease to liver disease to atherosclerosis," says Murthy. To test the ability of the DART send this protein in the liver, the researchers first injected mice with a high dose of the painkiller acetaminophen pain which is likely to cause liver damage. an hour later, they injected DARTs of Nrf2 bearing.
They found that the DARTs were taken up primarily in the liver and increase the expression of three genes known to protect against oxidative stress. liver samples of treated mice closely resembled DART those of healthy mice, while livers of untreated mice showed significant damage, the group announced online today Nature Materials .
These results are "quite dramatic "said José Manautou, a toxicologist at the University of Connecticut, Storrs, and treatment may be helpful for patients with acetaminophen overdose. But these patients usually arrive at the hospital a day after ingestion, not an hour, he said. Murthy's team is currently working on studies to see if the treatment can actually reverse existing damage, including the effects of chronic liver disease.
Others are much more interested in seeing DARTs work on other tissues. "It is relatively easy to get things made by liver cells," says David Frank, an oncologist at the Dana-Farber Cancer Institute in Boston. "It's always a bit the first step in a new technology delivery. "But he sees significant potential in cancer, for example, if a DART could incorporate a mutated version of a transcription factor that stops the genes that promote tumor growth.
groupMurthy has no immediate plans to work on targeting other tissues. the sugar they used in this study has a double objective at hand disrupt membranes and liver targeting. "in theory, you could do the same with peptides and antibodies and things like that, "he said," but the chemistry is going to get much more complicated. "
Tseng, who continued to work on its own transcription factor delivery method to reprogram adult cells into stem cells, is enthusiastic about the DART strategy. "We struggled trying to find a good way to apply this transcription factor Delivery of history," he said. "I could not think of anything better at this point." But he warned that the proteins they -Same are very expensive, which puts extra pressure on the use of transcription factor therapies. "If they work well, then I think the cost may not be the issue," he said, "but you need to find the key applications beyond the liver damage. "
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