In a presentation at the 8th Annual Asia TIDES: Oligonucleotide and Peptide Research, Technology and Product Development Conference in Kyoto, Japan, Bob D. Brown, Ph.D., chief scientific officer and senior vice president of research at Dicerna, presented a case study of the application of the GalNAc-DsiRNA-EX-Conjugate technology to a well-characterized hepatic disease gene, Alpha-1-antitrypsin (SERPINA1), resulting in a reduction of serum Alpha-1-antitrypsin (A1AT) in a transgenic mouse model of liver disease. GalNAc-DsiRNA-EX-Conjugates are being optimized for both SC and IV administration, Dr. Brown noted, adding that both routes of delivery have the potential to yield high bioavailability and efficient liver uptake at equivalent doses.
“Utilizing our proprietary technology, we have developed DsiRNA-EX-Conjugates that facilitate efficient delivery and gene target knockdown in the liver,” commented Dr. Brown. “Our GalNAc-DsiRNA-EX-Conjugates, with their ‘Tetraloop’ configuration, appear to offer numerous advantages including RNAi potency, nuclease resistance, and reduced immunostimulation, and the platform is remarkably tolerant of conjugate linker lengths and chemistries. The technology facilitates efficient design of therapeutic RNAi leads, and it potentially enables GalNAc-mediated subcutaneous or intravenous conjugate delivery to the liver, making possible a degree of flexibility not seen with other conjugate-based approaches.”
“Our DsiRNA-EX-Conjugate platform may establish a product engine for subcutaneous delivery of gene-targeted molecules,” commented Douglas Fambrough, Ph.D., chief executive officer of Dicerna. “This potential allows us to investigate, in parallel, potential therapies for use against a wide variety of liver targets for multiple disease indications.”
Dicerna has developed investigational DsiRNA-EX-Conjugates for liver-related diseases by attaching N-acetyl galactosamine (GalNAc) sugars to one or more points on DsiRNA-EX molecules, yielding multiple proprietary conjugate delivery configurations. The GalNAc sugars specifically bind to receptors on target cells, leading to internalization and access to the RNAi machinery within the cells.
Dr. Brown also presented data showing a greater than 75% reduction in serum A1AT in non-human primates treated with a prototype SERPINA1 GalNAc-DsiRNA-EX-Conjugate, with effects lasting more than seven weeks after the last of five SC doses.
“We are optimizing our DsiRNA-EX-Conjugates for four therapeutic liver targets, with additional programs planned,” Dr. Brown said. “We aim to increase our understanding of GalNAc conjugate medicinal chemistry through ongoing study of this unique therapeutic approach.”
Dr. Brown’s presentation will be available after 7:30 a.m. ET on Thursday, February 25, 2016 on the Events & Presentations page in the Investors & Media section of the Dicerna website.