Taking a step beyond RNA interference (RNAi), scientists have now developed a novel gene silencing platform that may enable the development and discovery of a new class of drugs to treat a wide array of diseases resistant to current RNAi.
Led by Rutgers' Samuel Gunderson, the researchers developed the technology with an approach to specifically target RNA biosynthesis.
The platform boasts very significant improvements over existing RNAi approaches.
RNA interference (RNAi) is a system within living cells that helps control which genes are active and how active they are.
The highly efficient gene silencing agents use a novel mechanism of action for their functioning.
The agents are single-stranded oligonucleotides, called U1 Adaptors, that have dual, and independent, functions. First is a target-gene binding domain that can be tailored to any gene. The second domain inhibits mRNA maturation by binding U1 snRNP, a component of the cellular splicing apparatus.
By combining both capabilities in the same molecule, the U1 Adaptor can inhibit the pre-mRNA maturation step of polyA tail addition in a gene specific manner.
Also, the domains of the oligonucleotide are independent, thus transcript binding and U1 snRNP binding can be independently optimised and adapted to a wide array of genes associated with disease.
"The U1 Adaptor platform expands on early technologies that used 5'-end-mutated U1 snRNA," Nature magazine quoted Gunderson an associate professor in the Department of Molecular Biology and Biochemistry at Rutgers, The State University of New Jersey, as saying.
He added: "The U1 Adaptor is an oligonucleotide version of this older method and instead targets the 3' end processing step. U1 Adaptors have high activity when used alone and are synergistic when used in combination with RNAi."
He also said that the range of possible targets was very broad due to the mechanism of action in which inhibition occurs during the biosynthesis of mRNA at the near universal 3' end processing step.
In his opinion, the most interesting aspect of this technology is that U1 Adaptors can possibly inhibit genes that do not respond to current RNAi methods.
The applications of U1 Adaptors expand on those currently available using standard RNAi approaches. They can be used as a research tool to determine gene function and to validate gene targets.
Gene silencing molecules also have potential prophylactic and therapeutic applications based upon ongoing clinical trials using RNAi and traditional antisense approaches.
The research findings have been reported in the online edition of Nature Biotechnology.