Early promise of new gout therapy

"A revolutionary treatment for gout could result in a new form of therapy for a range of other medical conditions – such as diabetes and obesity", The Independent reported. It said tests in mice found that implanting a small plastic capsule, which contained genetically engineered cells, under the skin could reduce symptoms of gout and potentially other metabolic diseases, such as diabetes or obesity.

This study has shown that it is possible to use a cell-based system that uses certain biological mechanisms to regulate levels of uric acid in mice. This is a fascinating development, but further research will be needed to see whether this system can be safely tested in humans.

The system developed in this study works specifically for uric acid, but it is possible that a similar approach could be used to control other compounds in the body. However, each compound will need its own system for monitoring and controlling its levels, and some compounds may be more difficult to control than others. Although diabetes may be a target for a similar approach, it is not yet clear if this will be possible.

Where did the story come from?

Dr Christian Kemmer and colleagues from ETH Zurich and other research centres in Switzerland and France carried out this research. The study was funded by the Swiss National Science Foundation and the EC. The research paper was published in the peer-reviewed scientific journal Nature Biotechnology.

The Independent correctly reported that this study was in mice and focused on uric acid metabolism. Although it may be possible to adapt this technique to treat conditions such as diabetes, the technique is in its early stages and has not yet been adapted for dealing with glucose or animal models of diabetes. Therefore, The Independent’s headline that the “Capsule offers hope to diabetes sufferers” seems premature.

What kind of research was this?

This aim of this research was to work towards creating a device that could maintain a steady level of uric acid in the blood, based on natural biological mechanisms. Uric acid is a chemical formed when proteins are broken down in the body. It is removed from the body in urine. Too much uric acid in the body can cause a condition called gout, where uric acid crystals form in the joints and cause pain.

Our bodies have many mechanisms for keeping chemicals such as uric acid at optimal levels. If these mechanisms go wrong, it can lead to imbalances in these chemicals and potentially disease. This study was carried out to show that it was possible to create a biologically based system that can sense and correct imbalances in uric acid in the bloodstream. If such a device were possible, the researchers hoped that the same principle could be applied to correct imbalances in other compounds, such as glucose levels in diabetics.

This type of research in animals is essential for the development of new treatments as such early research could not be carried out in humans. The technique will need to be refined in animals and shown to be effective and safe for any of the different conditions that it might be used for, before it could be tried in humans with these conditions. As the body controls the levels of different compounds in different ways, the technique would need to be adapted for each new compound and may not be as effective for all compounds.

What did the research involve?

The researchers first developed a system that could sense and respond to increases in uric acid in the blood. This system was based on a bacterial protein (called HucR), which, in the absence of uric acid, can switch off certain genes by binding to their DNA. When uric acid is present, the protein binds to the uric acid instead, releasing the DNA and allowing the gene to be active.

The HucR protein was adapted so that it would regulate the activity of a specific gene that produces urate oxidase, a protein that breaks down uric acid. The theory was that when uric acid levels were low, the HucR protein would bind to the urate oxidase gene and stop it from being active; when uric acid levels were high, the HucR protein would “release” the gene, allowing it to start producing urate oxidase to break down the excess uric acid. This effect needed to be reversible, so that once uric acid levels returned to normal, the HucR would bind to the urate oxidase gene again and stop it being active.

The researchers tested their system in human cells grown in the laboratory. They also genetically engineered the cells to produce a protein that transports uric acid into the cells, to make them more sensitive to the chemical.

Once the system had been demonstrated as working in cells in the laboratory, the testing progressed to mice that lacked their own urate oxidase. These mice developed high levels of uric acid in their blood and uric acid crystals formed in their joints and kidneys, causing symptoms similar to gout in humans.

The genetically engineered human cells were implanted into these mice. The researchers looked at what happened to the levels of uric acid in the blood and urine, and the uric acid crystals in their kidneys. They also compared these levels with levels in mice treated with allopurinol (a treatment used for gout that lowers the levels of uric acid) and in control mice implanted with cells that were not genetically engineered to regulate uric acid.

What were the basic results?

The researchers found that, in mice with high uric acid levels implanted with the genetically engineered cells, uric acid levels in the blood and urine were reduced to the same levels as mice treated with allopurinol. These levels were lower than the levels in control mice that were not implanted with engineered cells or treated with allopurinol.

The levels of uric acid seen in the blood in the mice was 5 milligrams per decilitre (mg/dl), lower than the 6 mg/dl needed for uric acid crystals to dissolve in humans. The mice treated with the genetically engineered cells also developed fewer uric acid crystals in their kidneys than the control mice.

How did the researchers interpret the results?

The researchers concluded that they have developed a cell-based implant system that can “provide self-sufficient and reversible control of uric acid levels in the bloodstream”. This can prevent the build-up of uric acid but also maintain normal baseline levels of uric acid. They say the system may be suited for treating and preventing conditions associated with high levels of uric acid in the body, such as gout. They also say that the basic principle of this system could motivate the development of similar systems to regulate other chemicals in the body.

Conclusion

This study has shown that components of biological systems can be used to make a synthetic cell-based system for controlling uric acid levels in the bloodstream in mice. This is a fascinating development and further research will determine whether the system can be used in humans. The technique is likely to require further testing of its efficacy and safety in animals before it could be tested for treating gout in humans.

The system developed here is specifically aimed at uric acid, but it is possible that a similar approach could be used to control other compounds in the body. However, each compound will need its own system for monitoring and controlling its levels, and some compounds may be more difficult to control than others. Therefore, although diabetes seems to be a potential target for a similar approach, it is not yet clear if this will be possible.