Wisconsin Alumni Research Foundation

Therapeutics & Vaccines
Therapeutics Vaccines
Compounds and Methods for Modulating Frataxin Expression in Friedreich’s Ataxia
WARF: P160232US07

Inventors: Aseem Ansari, Graham Erwin, Matthew Grieshop

The Wisconsin Alumni Research Foundation (WARF) is seeking commercial partners interested in developing new treatments for Friedreich’s Ataxia (FRDA), a terminal neurodegenerative disease with no effective therapy. UW–Madison researchers have developed synthetic transcription elongation factors (Syn-TEFs) for increasing frataxin (FXN) expression in FRDA patients.
Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder without treatments to halt or reverse disease progression, affecting roughly 9,000 Americans. FRDA is caused by triplet expansion in the first intron of FXN (which encodes the protein frataxin). Disease severity correlates with the number of repeats, with affected patients typically having 100s to 1,000s of triplet repeats.

FXN mRNA drops 90% in FRDA patients while genetic carriers exhibit expression levels at about 40% and normal function, indicating that lower expression is tolerable. Published work suggests that transcriptional elongation (overcoming ‘paused’ transcription processes) is the major hurdle to making sufficient FXN mRNA. To data, no intervention has sufficiently raised FXN mRNA to combat FRDA symptoms. In the present invention, the researchers focused on resolving the transcriptional pausing hurdle as a means to improve FXN mRNA production.
The Invention
UW–Madison researchers have generated new chimeric complexes that selectively increase FXN mRNA production to eliminate the physiological cause of Friedrich’s Ataxia. The synthetic transcription elongation factors (Syn-TEFs) of the present invention comprise a bromodomain inhibitor (such as Brd4), bound to a linker (such as PEG), which is further bound to a polyamide designed to target a gene sequence of interest near the repeats (see image below). Mechanistically, the complex binds selectively to the DNA near the triplet repeats in FRDA patients, and then the linked bromodomain inhibitor binds BRD4 and thereby recruits the elongation machinery to restart the paused transcription complex.

The inventors observed a 4.3-fold improvement at 500 nM after 1 day, which should be sufficient for real improvement, since FRDA carriers only have 40% of normal expression and show no symptoms. Increasing the dose to 1 μM increased FXN mRNA 8.5-fold after 1 day, with 3-fold improvement after only 6 hours.
  • Specific and potent activation of FXN gene expression
Key Benefits
  • Superior activation of FXN gene expression compared to existing approaches
Additional Information
For More Information About the Inventors
For current licensing status, please contact Rafael Diaz at [javascript protected email address] or 608-960-9847
Syn-TEF can be seen in brackets tethering transcription elongation machinery to the selective genomic location for improved FXN gene expression.