EXECUTIVE SUMMARY

Gene Silencing with U1 Adaptors

SUMMARY:  Dr. Samuel I Gunderson in the Department of Molecular Biology and Biochemistry at Rutgers University has developed an oligonucleotide-based method to reduce gene expression by inhibiting 3'-end formation during mRNA biosynthesis.  This method, called the “U1 adaptor”, 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-based (siRNA) approaches.  Siuta Consulting has been retained by Rutgers to identify partners for this technology.

BACKGROUND:  It has long been appreciated that gene expression can be regulated at the post-transcriptional level, defined to be the steps between transcription initiation and release of the nascent polypeptide from the ribosome.  Antisense based approaches encompass a broad variety of techniques but have in common that an oligonucleotide is designed to base pair with its complementary target mRNA or more broadly to any RNA leading to either degradation of the RNA or impaired function (e.g., translation).  Classical antisense approaches were designed to interfere with translation of the target mRNA or induce its degradation via Rnase H.  Ribozyme containing antisense molecules also can induce RNA degradation and have the advantage that they can be turned over, meaning re-used to cleave more RNA targets.  RNAi-based approaches have proven more successful and involve using siRNA to target the mRNA to be degraded.  However, some mRNAs are only modestly downregulated (2-fold) by RNAi and others are refractory.  Furthermore, none of these approaches has yet shown clear prophylactic or therapeutic benefits in patients.  Thus, there is still the need for more additions to our gene regulatory tool kit.

TECHNOLOGY:  The U1 adaptor is distinguished from and/or improves upon existing gene silencing technologies in the following ways:

1. The U1 adaptor separates into two independent domains the annealing (i.e., targeting) activity and the inhibitory activity allowing one to optimize annealing without affecting the inhibitory activity or vice versa.

2. As compared to these other technologies, a single U1 adaptor has a far higher level of inhibition and usage of two adaptors to target the same gene gives strong synergistic inhibition up to an unprecedented 700-fold level.

3. The U1 adaptor has a novel inhibitory mechanism, meaning it should in principle be compatible when used in combination with other methods.

4. The U1 adaptor inhibits the biosynthesis of mRNA by inhibiting the critical, nearly-universal pre-mRNA maturation step of polyA tail addition (also called 3' end processing).

PATENT STATUS:  A United States Provisional Patent Application was filed on March 29, 2007.