One‑Time Gene Therapy Enables Sustained Weight‑Loss Drug Production for Obesity & Diabetes

"A single gene therapy injection enables liver cells to continuously produce exenatide—an anti-obesity and anti-diabetic hormone—for months."
A single gene therapy injection enables liver cells to continuously produce exenatide—an anti-obesity and anti-diabetic hormone—for months. / Pexels 



Researchers at Osaka University have developed a groundbreaking once‑off gene therapy that reprograms the liver to produce exenatide, a GLP‑1 receptor agonist used in weight‑loss and diabetes treatments. Tests in diet‑induced obese and pre‑diabetic mice demonstrate long‑term appetite suppression, reduced weight gain, improved blood sugar control, and sustained exenatide production—all from a single injection  .

How It Works

  • Genome editing with HITI: Instead of correcting defective genes, researchers used homology‑independent targeted integration (HITI) via CRISPR‑Cas9 to insert a secretable exenatide gene into the albumin locus of liver cells  .
  • Lipid nanoparticles (LNPs) delivery: These carry plasmids encoding Cas9, guide RNA, and the exenatide gene to hepatocytes via one IV injection  .
  • Drug reservoir in liver: After integration, hepatocytes continuously secrete exenatide into the bloodstream for at least six months in mice  .

Key Findings

  • Treated mice consumed 29% less food and gained 34% less weight over 28 weeks  .
  • Improved glucose metabolism and insulin sensitivity; reduced HbA1c and fasting glucose comparable to lean mice  .
  • No adverse effects or liver enzyme abnormalities detected; minimal off‑target CRISPR events found via deep sequencing  .

Scientific Context & Comparisons

Conventional exenatide or GLP‑1 agonists are biologics requiring frequent injections due to short half‑lives. In contrast, this gene‑based approach maintains stable drug levels without repeat dosing  .

Earlier gene therapies (e.g., adenoviral GLP‑1 expression in 2007–2019) showed temporary diabetes reversal in mice  . However, the new LNP‑CRISPR‑mediated integration achieves >6 months of sustained therapeutic peptide secretion, with stronger safety and retention  .

Challenges & Next Steps

Despite only ~1% liver cell editing efficiency, metabolic benefits were significant  . Researchers now aim to refine targeting, evaluate immune responses, and test other animal models that better mimic human obesity before moving to clinical trials.

Conclusion

This innovative one‑time genome editing strategy fuses gene‑therapy and biologics to create a self‑sustaining “drug factory” in the liver. It holds immense potential for treating obesity, type 2 diabetes, and other chronic diseases that currently require lifelong injections.


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