Watertown, MA, United States
Watertown, MA, United States

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Patent
Kyowa Hakko Kirin Co. and Dicerna Pharmaceuticals | Date: 2017-04-12

The present invention provides a composition for suppressing the expression of the CKAP5 gene, the composition comprising a lipid particle containing a double-stranded nucleic acid as a drug and a cationic lipid,the double-stranded nucleic acid having an antisense strand having a base sequence complementary to the sequence of at least 19 continuous bases in CKAP5 gene mRNA of any one of SEQ ID NOs: 1 to 6,the cationic lipid being represented by formula (I):R^(1) and R^(2) are the same or different and are each linear or branched alkyl, alkenyl or alkynyl of 12 to 24 carbon atoms;L^(1) and L^(2) are the same or different and are each -CO-O- or -O-CO-;a and b are the same or different and are each 1 to 3; andR^(3) is a hydrogen atom, alkyl of 1 to 6 carbon atoms, or alkenyl of 3 to 6 carbon atoms;a medicament comprising the composition, and the like.


This invention relates to compounds, compositions, and methods useful for reducing MYC target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 184.13K | Year: 2015

DESCRIPTION provided by applicant c MYC has been recognized for three decades as a key oncogenic driver since the discovery of retroviral oncogenes their normal cellular counterparts and immediate early response genes that are activated in response to mitogenic factors A large fraction of all human cancers have also been shown to contain c MYC gene amplifications including of some hematologic tumors and up to of all solid tumors Genetically engineered tumors of multiple types have confirmed the profound roll of c MYC in tumor initiation and progression and down regulation of c MYC expression has shown significant therapeutic effects in many GEMM tumor types Unlike most successfully drugged disease causing proteins c MYC does not participate directly in a cellular signaling cascade as a receptor kinase or other signal transduction element and the protein has no known enzymatic activity or other function suitable for small molecule binding Due to the inherent difficulty in targeting protein protein and protein DNA binding interactions c MYC has remained undruggable by conventional approaches RNAi is a modality that can overcome the challenges of drugging the c MYC protein directly because RNAi targets and destroys messenger RNA in a sequence specific manner thus reducing target protein expression as a consequence of mRNA elimination RNA duplexes dissolved in infusion media and systemically administered as andquot freeandquot duplexes are ineffective as cancer therapeutic agents for three reasons rapid clearance from blood by renal filtration rapid degradation by ubiquitous nucleases in blood and lack of accumulation in tumor tissues One approach to overcome all three of these therapeutic limitations is to develop clinically acceptable nanoparticle formulations to efficiently deliver RN to tumors in vivo Lipid based nanoparticles are the most well established clinical stage formulations due to their similarities to approved liposomal drug products By focusing our research and development on tumor bearing animals we have developed both a novel lipid composition and manufacturing process that dramatically improves both efficacy and tolerability of LNPs for RNA delivery while minimizing inflammatory effects Thus our c MYC DsiRNA formulated in LNPs that mediate intratumoral delivery has the potential to yield a therapeutic response in up to of all cancer patients and with an acceptable therapeutic index In this application we seek to expand the therapeutic index of our experimental drug further enabling it to be used in patients highly compromised by their disease state prior therapies or in the case of hepatocellular carcinoma patients by underlying chronic liver disease Project Description Page PUBLIC HEALTH RELEVANCE We will optimize both the approved pharmaceutical ingredient in a DsiRNA based therapeutic targeting the cMYC oncogene and the lipid nanoparticle delivery system itself by using a new functional excipient


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2016

DESCRIPTION provided by applicant Hepatocellular carcinoma HCC is the third most common cause of cancer related deaths worldwide with the incidence increasing significantly in the West The prognosis for HCC is poor and the limited success of the standard of care drug sorafenib along with recent Phase III failures of other treatments underscores the need for novel HCC therapeutics Intrahepatic cholangiocarcinoma IHCC the second most frequent primary liver tumor is also associated with poor prognosis Colorectal cancer CRC is the fourth most common cause of cancer deaths throughout the world Despite the recent advances in treatment strategies post operative prognosis of CRC patients with liver lymph node or distant organ metastasis remains poor underscoring the need for novel therapeutics The Wnt signaling pathway is commonly activated in all three of these diseases and this is thought to be a causal event in their tumorigenesis In this application we continue the development of a lipid nanoparticle LNP platform using an RNAi based payload that targets a key component of the Wnt signaling pathway beta catenin CTNNB Beta catenin which is well validated as an oncology target with high clinical mutation occurrence and experimental evidence is considered undruggable via conventional approaches However by enabling pharmacological intervention at the mRNA level as opposed to the protein level our RNAi approach inhibits synthesis of beta catenin protein and causes tumor growth inhibition in preclinical models Building upon the successful development of our LNP encapsulated Dicer Substrate siRNA siRNA targeting the MYC oncogene we sought to improve LNP formulations and demonstrate effectiveness with a second payload delivering CTNNB to tumors Our in house experience with developing and cGMP manufacturing LNP formulated therapeutics as well as the similarities to approved liposomal oncology products led us to generate and characterize LNPs with unique chemical compositions carrying novel CTNNB DsiRNA payloads Here we demonstrate dramatic improvement in efficacy and other properties of tumor centric LNPs Through this work a formulated LNP CTNNB DsiRNA candidate that is suitable for preclinical development and IND submission has been identified In this application we seek to perform IND enabling studies process development and GMP manufacture of this candidate as well as perform translational research to guide the clinical research strategy The ultimate goal is to develop a Lipid Nanoparticle formulation that can be used to deliver a broad range of siRNA payloads with a tolerability profile to enable treatment of patients with a spectrum of disease states and prior therapeutic histories PUBLIC HEALTH RELEVANCE We will continue the preclinical development of lipid nanoparticle delivery platform demonstrating efficacy with a DsiRNA that targets the Wnt signaling pathway in tumors


This invention relates to compounds, compositions, and methods useful for reducing HIF-1 target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.


This invention relates to compounds, compositions, and methods useful for reducing -catenin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.


This invention relates to compounds, compositions, and methods useful for reducing -catenin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.


This invention relates to compounds, compositions, and methods useful for reducing C5 target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.


This invention relates to compounds, compositions, and methods useful for reducing -catenin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.


Patent
Dicerna Pharmaceuticals | Date: 2015-09-11

Formulations comprising anionic agents such as nucleic acids within a lipid-containing particle methods of formulating a lipid-containing particle comprising an anionic agent such as a nucleic acid, methods for preparing a lipid-containing particle comprising an anionic agent such as a nucleic acid, methods for therapeutic delivery of an anionic agent to a patient in need thereof, where the anionic agent is formulated in a lipid-containing particle as described herein.

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