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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Gene therapy reverses obesity in mice

A research study has successfully tested a gene therapy approach that could specifically reduce fat tissue and reverse obesity-related metabolic disease in obese mice.

Obesity is a leading preventable cause of death worldwide, and results from an interplay between genetic and environmental factors. Despite significant progress in understanding the molecular mechanisms of obesity, the currently available anti-obesity drugs have shown limited efficacy with severe side effects.

In the present study published in Genome Research, Prof. Yong-Hee Kim and team at Hanyang University (South Korea) developed a targeted gene silencing therapy against a fatty acid metabolism gene, Fabp4, to treat obesity and obesity-induced type 2 diabetes. They used a CRISPR interference mechanism wherein catalytically dead Cas9 and single guide RNA were combined with a non-viral gene delivery system to target it to the white adipocytes using tissue-specific marker of adipose tissue, prohibitin.

The complex was found to internalize into the white adipocytes with little toxicity and upon entry, it selectively decreased the expression of Fabp4 and reduced lipid storage in white adipocytes. Having successful in vitro, the team then tested the approach in obese mice. Mice were fed a diet high in fat leading to obesity and insulin resistance. Using the CRIPSR approach resulted in 20% reduction of body weight and improved insulin resistance and inflammation after just six weeks of treatment.

Findings from the study provide early evidence for the use of CRISPR-based precision gene editing technology in treating obesity and obesity-induced metabolic syndromes. The significance of the study lies in the fact that current standard FDA-approved treatment only showed 5% reduction of body weight in humans one year after treatment, while this study showed 20% reduction in mice. Although further studies are required before it can be used in clinic for humans, the approach shows promise and can be translated to other types of therapies.

Source: Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance. Chung JY et al., Genome Research, August 2019. DOI

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