Genetic disease drug discovery – utilising
frameshift to overcome stop-codon mutation
Technology Type: drug discovery tool
Synopsis:. In some genetic diseases, a point mutation can lead to the introduction of a stop codon
leading to premature termination of translation and to truncated and non-functional proteins. If
drugs could be found that enhance readthrough to overcome this premature termination of protein
synthesis, a functional protein could be maintained despite the mutation. There are several human
diseases caused by genetic mutations where a stop codon occurs in the middle of gene responsible
for functional proteins. Examples are 10-20% of patients with Duchenne muscular dystrophy (DMD),
10% of cystic fibrosis, Hailey-Hailey disease, Factor VIII deficiency, Cystinosis and others.
Department: Biochemistry, Dunedin Campus
Partners: An application to DMD is currently pursued in partnership with the Walter + Eliza Hall
Institute (WEHI, contact: Dr Kurt Lackovic) in Australia (high
throughput screening and medicinal chemistry) and with the
Murdoch Childrens Research Institute (MCRI, contact: Dr James
Dromey) also in Melbourne (DMD animal models and patients).
Feature Technology: Professor Warren Tate (Rutherford Medal
2010) discovered the frameshift mechanism originally in bacteria
almost 30 years ago and since then has accumulated significant knowledge on ribosomal frameshift
and its biological context. Otago’s patented frameshift drug discovery test system is a cell based
assay taking its biological context into account whilst screening for hits. This also allowed exclusion
of all effective hits that showed any signs of ribosomal or cell toxicity. The cell based assay has been
validated for the HIV target with a HIV sequence inserted providing opportunities for HIV frameshift
modulation. In collaboration, WEHI’s drug like compound library of 113,000 compounds has been
screened, resulting in 125 promising hits. Five of the best compounds selected from 18 validated
performing compounds are now being pursued more rigorously. Otago’s assay has also been
amended to include human sequences that are essential to the mutation in Cystic Fibrosis. A pilot
screen of 140 drug-like compounds has been conducted in collaboration with WEHI. The system is
currently amended to its application in DMD in partnership with WEHI and MCRI. Many other
opportunities to apply this screening tool are still available for partnering.
Commercial Opportunity: License, investment or other partnership to allow application of this
useful tool to target specific stop-codon mutations in (rare) genetic disorders.
Key Contact: Alex Tickle