Researchers at Hanyang University, South Korea, have used the gene-editing technology CRISPR-Cas9 to treat obesity and type 2 diabetes in mice, a development that could eventually benefit humans. The therapy specifically reduced fat tissue and reversed obesity-related metabolic disease in the animals.
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Jee Young Chung and colleagues say the technique could one day be used to treat people with type 2 diabetes and other obesity-related health problems such as stroke, heart disease, and cancer.
The obesity epidemic
Obesity is an increasing problem in developed countries, with the epidemic affecting almost half a billion people globally, many of whom are children. In the United States, the average weight of men is 197.8 pounds and for women, the figure is 170.5 pounds. Furthermore, an alarming 40% of adults in the country are classified as obese.
Obesity-related conditions such as heart disease, type 2 diabetes, stroke, and cancer are all leading causes of preventable death. Since obesity in humans develops as a result of both genetic and environmental factors, developing effective treatments is challenging.
Despite the major progress that has been made in understanding the molecular mechanisms underlying obesity, currently available anti-obesity therapies exhibit limited efficacy and severe side-effects. One study showed that the standard FDA-therapy only reduced body weight by 5% after a whole year of treatment.
Using CRISPR-Cas9 to tackle the problem
As reported in the journal Genome Research, Chung and team have now demonstrated that they can use CRISPR-Cas9 to reduce the bodyweight of obese mice by an impressive 20 percent. To put this into perspective, even just a 10% reduction would help obese humans to maintain a weight that is within a healthy range, whilst on their existing diet.
Since the advent of CRISPR, which alters sequences of DNA in order to enhance or silence the expression of specific genes, researchers have been using the tool to find out how it could be used to treat health problems in humans.
Chung and team used a CRISPR interference (CRISPRi) system to treat obesity and obesity-induced diabetes in mice. The mechanism was based on catalytically dead Cas9 and single guide RNA which were combined with a targeted non-viral gene delivery system.
The gene silencing therapy specifically targeted a fatty acid metabolism gene called Fabp4.
The CRISPRi technique utilized a vascular and cellular marker of adipose tissue, called prohibitin, to deliver the single guide RNA to mature white adipocytes. Internalization of the complex causes little toxicity to cells while decreasing the expression of Fabp4 and reducing lipid storage in adipocytes.
After demonstrating that this targeted delivery worked well in cells, the team tested the method in mice that had been fed a high-fat diet to make them obese. The mice also had insulin resistance.
The technique successfully reduced fat storage and induced weight loss
Delivery of the CRISPRi system to white adipocytes effectively silenced the expression of Fabp4, which reduced the amount of fat stored and caused a 20% reduction in body weight, compared with mice that did not undergo the therapy.
It also lowered indicators of type 2 diabetes such as high glucose levels, insulin resistance, hepatic steatosis, and inflammation. All of these beneficial effects were observed after just six weeks of treatment.
Additional systemic improvements included reduced fatty lipid deposition in the liver and lower levels of circulating triglycerides. Furthermore, these significant beneficial health effects were achieved without food intake being reduced or the mice being made to exercise.
This RNA-guided DNA recognition platform provides a simple and safe approach to regress and treat obesity and obesity-induced metabolic syndromes.”
Further studies needed and clinical trials are still years away
Although the therapy displayed promising results in mice, only five mice were used in each of the experimental and control groups. Further studies are therefore required before it can be used in the clinical treatment of human disease, but human trials will probably not be conducted for several years. In the meantime, people wanting to lose weight should carry on following diets that have been proved to help reduce obesity.
Importantly, the research highlights the progress that has been made in precision gene editing technology, which has implications for other types of therapies.
Chung, J. Y. (2019). Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance. Genome Research. https://genome.cshlp.org/content/early/2019/08/17/gr.246900.118.abstract