Illustration of adjustable dose gene therapy for diabetes and obesityIntroduction

Gene therapy has great potential but faces challenges such as fixed dosing, high costs, antigenicity, and systemic toxicity. Researchers from Remedium Bio have developed the first adjustable dose gene therapy platform addressing these issues with optimized specificity, localized delivery, high biocompatibility, and lower costs. They tested this innovative approach in a mouse model of type 2 diabetes (T2D) to evaluate its efficacy.

Pioneering Gene Therapy Approach

At the core of this breakthrough lies a specially designed lipid nanoparticle (LNP) driven delivery of GLP-1 DNA. Extensive characterization confirmed its high transfection efficiency in human adipocytes and pre-adipocytes (over 81%) without compromising cell viability. In vivo studies in mice demonstrated durable localized adipocyte-specific expression over 6 months with no detectable transgene presence in the liver, heart, spleen, or kidneys. Crucially, the transgene expression could be adjusted using physical (cryolipolysis, focused ultrasound) and pharmacological (inducible suicide gene) means – a first for gene therapy.

Methods

C57BL/6 mice were fed either a low-fat or high-fat diet followed by low-dose streptozotocin (40 mg/kg BW) to induce T2D. T2D mice were treated subcutaneously with LNP-GLP1, LNP-EX4, or vehicle. Animals were followed for 14 weeks during which body weight, glucose tolerance test (GTT), and insulin tolerance test (ITT) were measured.

Results

When applied to a high-fat diet and low-dose streptozotocin-induced T2D mouse model, a single treatment regimen expressing the genes for exenatide (EX4) or GLP-1 (glucagon-like peptide-1) led to:

  • Pronounced weight loss: 20% (LNP-GLP1) and 14% (LNP-EX4) at 4 weeks relative to vehicle.
  • Improved insulin response: 25% (LNP-GLP1) and 22% (LNP-EX4) reduction in ITT.
  • Better glycemic control: 37% (LNP-GLP1) and 38% (LNP-EX4) reduction in fasting glucose; 29% (LNP-GLP1) and 26% (LNP-EX4) reduction in the area under the curve of GTT.

The transgene was localized to the injection site with no detection in the liver, heart, spleen, or kidney. There were no significant changes in systemic markers of inflammation (IL-6 and TNF-α) or liver damage (ALP).

Conclusion

This first-in-class adjustable dose gene therapy platform represents a paradigm shift in the field. By overcoming major limitations around dosing, costs, and safety, it opens up possibilities for treating a wide range of common diseases that were previously inaccessible to gene therapy. The study demonstrates the ability of novel incretin gene therapy delivered by LNP to induce weight loss, improve insulin resistance, and enhance glycemic control in T2D.

References

  1. An adjustable gene therapy platform technology- PrometheusTM Link
  2. A Novel Gene Therapy Platform Using GLP1 and EX4 Attenuates Hyperglycemia in a Preclinical Model of Type 2 Diabetes. Link

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