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Genetic Assay for Transcription Errors: Methods to Monitor Treatments or Chemicals that Increase the Error Rate of RNA synthesis

Summary
Researchers at the National Cancer Institute (NCI) developed a genetic assay for detecting transcription errors in RNA synthesis. This new assay extends the familiar concept of an Ames test which monitors DNA damage and synthesis errors to the previously inaccessible issue of RNA synthesis fidelity. The FDA requires genetic DNA focused tests for all drug approval as it assesses the in vivo mutagenic and carcinogenic potential of a drug. The new assay will open an approach to monitoring the impact of treatments on the accuracy of RNA synthesis. Errors in transcription have been hypothesized to be a component of aging and age-related diseases. The National Cancer Institute (NCI) seeks licensing partners for the genetic assay.
NIH Reference Number
E-237-2016
Product Type
Keywords
  • Assay
  • Genetic Assay
  • Cre
  • Transcription Errors
  • Mutagenic Detection Method
  • Drug Screen
  • RNA
  • RNA Synthesis
  • Drug Therapies
Collaboration Opportunity
This invention is available for licensing.
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Description of Technology

Transcription errors in RNA, though rare and transient, lead to synthesis of defective proteins and RNA mediated regulation.  Errors in RNA transcription can cause many human diseases, including those that are age-related. 

Researchers at the National Cancer Institute (NCI) and Center for Cancer Research, RNA Biology Laboratory have developed a genetic assay that detects RNA synthesis errors. The new assay can detect the transient errors in transcription as permanent genetic changes.  Thus, it has the potential to test the level of transcription error-related toxicity caused by therapeutic compounds and prevent excessively toxic drugs from entering the market.

The assay is based on suppression of a mutation in the Cre recombinase, coupled with a Cre genetic reporter to monitor the activity of the recombinase. The Cre mutation results in an inactive enzyme; errors in RNA transcription of the Cre mutation transiently restores the activity of the enzyme. Additionally, the genetic reporter of Cre activity leads to permanent expression of a yellow fluorescent protein (YFP) and the mouse cell line in the invention assay has both the cre mutation source and cre activatable YFP gene. Activation of the YFP gene allows for the detection of transcription errors following exposure of the cells to compounds or other treatments. For example, exposure of the cells to elevated levels of manganese results in an increase of YFP expressing cells; these results are consistent with in vitro experiments demonstrating manganese can reduce transcription accuracy.  The mouse cell lines were derived from transgenic mice allowing for the follow up of results in live mice carrying the assay reporters.

Researchers at the NCI seek licensing partners for the assay which detects errors in RNA synthesis caused by carcinogens or therapeutic candidates.

Potential Commercial Applications
  • Assay to screen against drugs that can potentially cause RNA transcription errors
  • Assay to test the level of transcription error-related toxicity caused by therapeutic compounds and carcinogens

 

Competitive Advantages
  • Genetic assay for detecting errors in synthesis at the RNA level
  • First of its kind approach to monitoring mRNA synthesis errors and identifying drugs that could potentially increase the rate of transcription errors.
  • Proof of principle: Exposure of the cells to elevated levels of manganese results in an increase of YFP expressing cells; these results are consistent with biochemical experiments demonstrating manganese reduces transcription accuracy.
Inventor(s)

Jeffrey Strathern (NCI), Mary Ernst (NCI), Alison Rattray (NCI)

Development Stage
Patent Status
  • U.S. Provisional: U.S. Provisional Patent Application Number 62/480,747, Filed 03 Apr 2017
Therapeutic Area
Updated
Friday, May 4, 2018