Gene therapy delivers lasting weight loss, metabolic benefits in PWS mice
Study: One-time treatment reduced fat mass, blood sugar levels
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Researchers have developed a one-time gene therapy that may help ease obesity and related metabolic problems in people with Prader-Willi syndrome (PWS), according to a study in a mouse model of the disease.
A single injection of the therapy, which uses a harmless version of the adeno-associated virus (AAV) to deliver the gene encoding the exendin-4 molecule, significantly reduced the animals’ body weight, fat mass, and blood sugar (glucose) levels, with effects lasting several months.
“These data demonstrate the therapeutic potential of a systemic [body-wide] AAV-mediated exendin-4 gene therapy for PWS-related metabolic abnormalities in [a PWS] model,” researchers wrote.
The study, “Low dose systemic AAV-exendin-4 gene therapy for Prader-Willi syndrome and dietary obesity,” was published in Molecular Therapy Advances.
Evidence of GLP-1RAs as a treatment for PWS obesity is mixed
PWS is a rare genetic disorder caused by the loss of function of certain genes on chromosome 15. One of its hallmark symptoms is hyperphagia, an abnormally strong, persistent drive to eat, which can lead to severe obesity. Current strategies such as diet, exercise, and restricting food access are difficult to maintain and can trigger behavioral challenges.
GLP-1 receptor agonists (GLP-1RAs) are a class of drugs that mimic the effects of GLP-1, a hormone secreted by the gut in response to food intake. GLP-1 coordinates nutrient absorption and signals feelings of fullness.
To date, multiple GLP-1RAs have received regulatory approval for the management of type 2 diabetes and weight loss, including semaglutide, marketed under the brand name Ozempic.
As a treatment for obesity in PWS, however, the evidence is mixed, and data in PWS animal models are lacking. Moreover, GLP-1RAs typically require repeated injections over an extended period, raising concerns about treatment adherence, side effects, and costs.
Researchers at The Ohio State University developed a one-time gene therapy with the goal of promoting sustained production of a GLP-1RA in the body.
Dubbed Rec2-Ex4, the therapy uses a lab-made AAV form called Rec2 to deliver the gene encoding exendin-4 (Ex4), a protein similar to GLP-1, to liver cells, where it’s secreted into the bloodstream. They tested the gene therapy in a PWS mouse model lacking the Magel2 gene, which is involved in weight control and is defective in PWS.
PWS mice were much heavier than healthy mice before treatment
Before treatment, PWS mice were significantly heavier than healthy mice. After a single abdominal injection of Rec2-Ex4, PWS mice experienced significant weight loss, and their body weights moved closer to those of healthy mice. The therapy had a less pronounced effect on the body weight of healthy mice.
Four weeks after injection, PWS showed better control of glucose levels that closely resembled that seen in healthy mice. At the same time, food intake and energy expenditure showed no significant treatment effects.
When researchers used an imaging technique to assess the animals’ body composition, the excess fat mass in PWS mice was reversed by Rec2-Ex4 treatment. And relative lean mass, the proportion of lean mass relative to body weight, rose after Rec2-Ex4 treatment in both PWS and healthy mice.
PWS mice showed increased brown adipose tissue, a type of fat that generates heat, and areas of white adipose tissue for fat storage, ranging from 72% to 163% above healthy levels. Rec2-Ex4 treatment reversed these increases.
Consistent with the therapy’s mechanism of action, Ex4 was detected in the blood of treated PWS and healthy mice.
We present preclinical data that suggest [abdominal] administration of Rec2-Ex4 gene therapy at a low dose normalizes PWS-related metabolic abnormalities in [PWS] mice. These proof-of-concept data indicate Rec2-Ex4 as a potential molecular therapy for genetic and acquired forms of obesity.
Other blood tests showed that PWS mice had 3.4 times as much leptin (a hormone produced by fat cells that signals fullness) as healthy mice, a difference that was reversed by Rec2-Ex4 treatment. The adiponectin/leptin ratio, a marker of metabolic health in which lower values indicate increased risk of metabolic conditions, was significantly increased by treatment.
Behavioral tests showed that Rec2-Ex4 treatment improved exploratory activity in PWS mice, but had no significant effect on anxiety-like behavior.
Rec2-Ex4 was also tested in healthy mice fed a high-fat diet, a model for common obesity. Treated mice showed a significant reduction in body weight, relative fat mass, and food intake, as well as significant improvements in glucose control and exploratory behaviors.
By 21 weeks, three of the five untreated PWS mice had died, likely from obesity-related complications, while all treated mice remained healthy. Untreated PWS mice also showed severe fat buildup in the liver, which was completely absent in treated mice.
“We present preclinical data that suggest [abdominal] administration of Rec2-Ex4 gene therapy at a low dose normalizes PWS-related metabolic abnormalities in [PWS] mice,” the team wrote. “These proof-of-concept data indicate Rec2-Ex4 as a potential molecular therapy for genetic and acquired forms of obesity.”
