RheoSwitch® Controlled Gene Expression

Intrexon’s RheoSwitch® technology is a gene switch activated by a small molecule ligand which can be used to regulate the timing, location, and concentration of gene expression with potential applications in human, animal, and plant systems.  Precise control over in vivo gene expression with RheoSwitch® technology contributes multiple benefits, including a desirable safety profile for gene and cell-based therapies.  Human therapeutic product candidates using RheoSwitch® technology (referred to as RheoSwitch Therapeutic System® or RTS®) are currently in phase 1/2 clinical trials for melanoma and breast cancer.  Compelling clinical activity was recently reported in the melanoma study.

To enable inducible control over cellular function and optimized biological activity, the RheoSwitch® technology is fully integrated into Intrexon’s UltraVector® platform, an operating system comprising advanced DNA construction technologies, cellular and protein engineering, computational models and statistical methods which facilitate the rapid design, testing and production of complex biological systems.

The RheoSwitch® technology is a transcriptional regulator defined by three essential elements:
  1. Switch Components: a Co-Activation Partner (CAP) and a Ligand-controllable Transcription Factor (LTF), which form unstable and unproductive heterodimers in the absence of ligand.
  2. Activator Ligand: an ecdysone analog (a non-steroid small molecule), which serves as the activator. In presence of the ligand, the LTF and CAP change to stable conformation in a protein complex bound to the inducible promoter.
  3. Inducible Promoter: customizable promoter which binds the LTF and to which basal transcription proteins are recruited.

Intrexon’s RheoSwitch® technology enables expression of transduced genes only when the small molecule activator ligand combines with the switch components (CAP and LTF) and constitutively produced basal transcription factors, activating gene transcription from an inducible promoter, and ultimately resulting in expression of desired proteins.  The timing, location, and concentration of gene expression can be regulated in a dose dependent manner with RheoSwitch® technology and activator ligand.

Clinical data have shown an excellent safety profile for Intrexon’s oral activator ligand (INXN-1001; also known as veledimex) with no dose-limiting toxicity or maximum tolerated dose identified and no off-target pharmacodynamics observed.  In fact, the RheoSwitch® technology is predicted to provide benefits in all gene therapy paradigms.  The RheoSwitch® technology provides both a safety “off switch,” as well as a mechanism for titrating therapeutic effect on a patient-specific basis independent of gene delivery variability.

The RheoSwitch® technology may be most useful in treatments which require tightly controlled induction of protein and/or bioactive RNA expression levels.  Use of this technology allows drug developers and physicians the ability to control the timing, location and expression levels of intracellular and secreted therapeutic effectors by regulating the timing and dose of ligand administration.  RheoSwitch® controlled in vivo protein expression avoids toxicities caused by bolus dosing.

Additionally, inducible controlled gene expression may have applications in animal health and agriculture.  As with human therapies, treatments in animals require safety considerations for dosing and therefore would likely benefit from RheoSwitch® regulated therapeutic gene expression.  Further, inducible regulation of gene expression pathways could be employed in plants for adaptation to varied environmental and stress conditions.  Intrexon’s RheoSwitch® technology can be applied in both mammalian and plant systems for expression control with the goal of generating desired biological outcomes for potential product development.
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