Data Show Robust Silencing of CTNNB1 Gene in Patient-Derived Xenograft and Other Cancer Models Using RNAi
The data are being presented at the 2015 RNA & Oligonucleotide Therapeutics Meeting at
The findings demonstrate CTNNB1 DsiRNA's favorable pharmacokinetic (PK) and biodistribution properties as well as robust messenger RNA (mRNA) knockdown and tumor exposure in models of HCC, CRC, melanoma, leukemia, genetic hepatoblastoma, and other tumor types including PDX models.
"Dicerna's second generation EnCore LNP system has been further refined and is more broadly active than the first generation EnCore technology," said
In an orthotopic HCC PDX model, a single dose of CTNNB1 DsiRNA yielded up to 90% knockdown of CTNNB1 and downstream effectors. Furthermore, Dicerna scientists observed rapid dampening of Wnt signaling in the tumor cells, but not in the adjacent normal liver tissue.
In addition to the HCC findings, Dicerna showed mRNA knockdown in models of hepatoblastoma, melanoma, leukemia and CRC, providing further insights into the efficacy and delivery of EnCore mediated CTNNB1 DsiRNA in other tumor types. In one example, CTNNB1 DsiRNA delivery resulted in robust tumor growth inhibition in β-catenin-dependent CRC tumors.
Dicerna continues to advance its EnCore LNP platform through extensive structure-function analyses to identify advanced formulation components and manufacturing processes. These advances have yielded a greater mechanistic understanding of tumor delivery, improved potency, and up to 10-fold improvements in tumor-specific delivery.
RNA interference (RNAi) is a highly potent and specific mechanism for regulating the activity of a targeted gene. In this biological process, certain double-stranded RNA molecules known as short interfering RNAs (siRNAs) bind to complementary messenger RNAs (mRNAs) and recruit proteins that break the chemical bonds that hold mRNAs together, preventing the mRNAs from transmitting their protein-building instructions.
RNAi therapeutics have the potential to treat a number of human diseases by "silencing" disease-causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine.
About Dicer Substrate Technology
Dicerna's proprietary RNAi molecules are known as Dicer substrates, or DsiRNAs, so called because they are processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna's discovery approach is believed to maximize RNAi potency because the DsiRNAs are structured to be ideal for processing by Dicer. Dicer processing enables the preferential use of the correct RNA strand of the DsiRNA, which may increase the efficacy of the RNAi mechanism, as well as the potency of the DsiRNA molecules relative to other molecules used to induce RNAi. Dicerna's DsiRNA Extended (DsiRNA-EX) molecules resemble DsiRNA molecules but have an extended region at one end of the molecule which is engineered to provide additional functionality to the DsiRNA-EX molecules. Dicerna can also use this extended region to generate its DsiRNA-EX-Conjugates, where a drug delivery agent is linked directly to the extended region of the DsiRNA-EX molecule, enabling the ability to deliver DsiRNA-EX Conjugates to patients through a subcutaneous injection.
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Applicable risks and uncertainties include those relating to our preclinical research and other risks identified under the heading "Risk Factors" included in our most recent Form 10-Q filing and in other future filings with the
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