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Area of Science:

  • Synthetic Biology
  • Molecular Engineering
  • Pharmacology

Background:

  • Current synthetic gene switches have clinical limitations including cytotoxicity and side effects.
  • Acetylsalicylic acid (aspirin) is a safe, multifunctional drug with therapeutic benefits.

Purpose of the Study:

  • To develop a novel synthetic gene switch platform, ASPIRIN, activated by aspirin.
  • To engineer plant salicylic acid receptors for enhanced aspirin sensitivity.
  • To demonstrate in vivo efficacy in a diabetic mouse model.

Main Methods:

  • Repurposing and engineering plant salicylic acid receptors (NPR1, NPR4).
  • Constructing the ASPIRIN system with domain truncations and mutant screening.
  • Utilizing a membrane-tethering signal (myristoylation) and DNA-binding/activation domains.
  • Testing in microencapsulated cells within male diabetic mice.

Main Results:

  • The ASPIRIN system demonstrates aspirin-inducible gene expression.
  • Aspirin administration in diabetic mice restored normoglycemia.
  • The system alleviated pain and reduced inflammation and neuropathy biomarkers.

Conclusions:

  • The ASPIRIN platform offers a safe and effective method for small-molecule-regulated gene expression.
  • This system holds potential for developing aspirin-based combination gene therapies.
  • Repurposing plant receptors provides a novel strategy for drug-inducible gene switches.