Is Gene Editing The Answer To Obesity?

Losing weight, especially lots of it, is a big pain both physically and mentally.

Apart from diet and exercise, the traditional routes for losing weight, there’s also medicine. Prescription weight loss medications are still popular as part of a weight management plan. These drugs, however, carry with them a considerable risk of side effects. Chief among these undesirable consequences are dizziness, nausea, vomiting, constipation and insomnia, according to a 2016 study published in the American Journal of Medicine.

A new study directed at using genetic tools to combat obesity said anti-obesity drugs under development are directed at restricting caloric intake by acting on the gastrointestinal (GI) tract or the central nervous system (CNS). Both are delicate systems that can screw up the entire body if abused, hence, the low efficacy of anti-obesity drugs.

“However, most of these drugs have shown little efficacy accompanied by severe side effects," said the study whose corresponding author is Yong-Hee Kim, a professor in the Department of Bioengineering at Hanyang University in Seoul, South Korea.

This new study focuses on avoiding the side effects associated with anti-obesity drugs. More important, it wants to improve weight loss by exploiting our genetic code.

South Korean researchers led by Kim decided to use a modified CRISPR gene editing tool called “CRISPR interference (CRISPRi),” first developed by scientists at the University of California in San Francisco in 2013, in their experiment.

Traditional CRISPR seeks to alter the genetic code permanently. On the other hand, CRISPRi only interferes with gene expression by inhibiting the production of proteins. Therefore, the purpose of CRISPRi is regulation of the genome instead of modification. Using CRISPRi can either activate or repress gene expression.

In the CRISPRi system, scientists co-express a catalytically dead Cas9 (dCas9) lacking endonuclease activity with the gRNA. The gRNA is complementary to the region of the gene of interest you wish to repress or activate.

In a previous study, Kim developed a method to deliver genetically modifying agents to white fat cells, or adipocytes. In this new study, Kim explains adipocytes are difficult cells to target with these gene editing tools.

But using a short peptide that specifically docks with white adipocytes delivered the CRISPRi components to 99 percent of cells in a cell culture model.

For the experiment, a fatty acid-binding protein called “4 (fabp4)” was targeted. Scientists believe this protein plays a role in sugar and insulin metabolism. Significant amounts of fabp4 are present in white fat and plasma.

Reducing the levels of fabp4 in diabetic mice using an antibody resulted in improvements in blood sugar levels, as well as in fat and insulin metabolism, according to another study.

By resorting to their CRISPRi technology, Kim and his team were able to reduce the expression level of fabp4 by up to 60 percrnt.

The team then tested mice that were obese and diabetic. These mice were injected with peptide-targeting CRISPRi twice a week for up to 6 weeks. The mice lost some 20 percent of their body weight during this time.

"No significant changes in food intake were recorded during the treatment period, indicating that the loss of body weight is not due to eating less," the authors wrote.

Researchers also noted lower blood glucose levels, less inflammation and improved biomarkers of nonalcoholic fatty liver disease.

The study was small. It only included five mice in each experimental group. The study does, however, show the way towards further research into approaching obesity from a different angle than a traditional pharmaceutical approach.

"Despite its therapeutic potential, the translational research from a mouse model to patient in real life is yet a hurdle to overcome," the authors commented in the paper.

"In the in vivo experiments, the formulations were administered twice a week for up to 6 weeks. For humans, we cannot be sure whether a regimen of twice a week for up to 6 weeks could be applied," they continued.

The study concluded further studies about the translational research from a mouse model to human patient definitely need to be carried out before clinical use.