Compositions and methods for silencing aldehyde dehydrogenase

一种醛脱氢酶、组合物的技术，应用在用于沉默醛脱氢酶的组合物和方法领域，能够解决低病人依从性、双硫仑限制、不常见等问题

Inactive Publication Date: 2014-10-22
PROTIVA BIOTHERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, disulfiram has clinical limitations due to low patient compliance, and a series of side effects such as drowsiness, headache, and less commonly neurotoxicity
To be effective, disulfiram is usually administered daily, and therefore it is easy for the patient to discontinue the drug

Method used

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  • Compositions and methods for silencing aldehyde dehydrogenase
  • Compositions and methods for silencing aldehyde dehydrogenase
  • Compositions and methods for silencing aldehyde dehydrogenase

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0321] VI. Preparation of Lipid Particles

[0322] Lipid particles of the invention, e.g., SNALPs, wherein nucleic acids such as interfering RNA (e.g., siRNA) are embedded within the lipid portion of the particle and protected from degradation, can be formed by any method known in the art, the Methods include, but are not limited to, continuous mixing, direct dilution, and in-line dilution.

[0323] In specific embodiments, the cationic lipid may comprise a lipid of Formulas I-III or a salt thereof, alone, or in combination with other cationic lipids. In other embodiments, the non-cationic lipid is egg yolk sphingomyelin (ESM), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), 1-palmitoyl-2-oleoyl - Phosphatidylcholine (POPC), dipalmitoyl-phosphatidylcholine (DPPC), monomethyl-phosphatidylethanolamine, dimethyl-phosphatidylethanolamine, 14:0PE (1,2-dimyristoyl- Phosphatidylethanolamine (DMPE)), 16:0PE (1,2-dipalmitoyl-phosphatidylethanolamine (DPPE)),...

Embodiment 1

[0387] This example demonstrates that serum stable nucleic acid-lipid particles (SNALPs) containing siRNA targeting ALDH2 reduce aldehyde dehydrogenase 2 gene expression in murine hepatic cell lines in vitro.

[0388] Material:

[0389] All siRNA molecules used in these studies were chemically synthesized and annealed using standard procedures.

[0390] siRNA sequences targeting aldehyde dehydrogenase 2 (ALDH2) used in this study:

[0391]

[0392] where 'r' denotes ribonucleotides, 'm' denotes 2'-O-methylated ribonucleotides, and without any prefix denotes deoxynucleotides.

[0393] Additionally, non-targeting siRNA was included in the study as a control. This siRNA targets the firefly luciferase gene and is not intended to have any specific gene silencing activity in mammalian cells.

[0394] method:

[0395] Nucleic acid-lipid particles consisted of the following "1:57" formulation: 1.4% PEG2000-C-DMA; 57.1% DLinDMA; 7.1% DPPC; and 34.3% cholesterol. Typically, in a...

Embodiment 2

[0405] This example shows that SNALP comprising siRNA targeting ALDH2 reduces aldehyde dehydrogenase 2 gene expression in a whole animal system by the intravenous route of administration.

[0406] Material:

[0407] The mouse ALDH-2 siRNA duplex 1 and non-targeting control siRNA used in this study are described in Example 1.

[0408] method:

[0409] SNALP formulations were prepared as described in Example 1.

[0410] Animal Handling:

[0411] Female BALB / c mice were obtained from Harlan Labs. Animals were administered a single dose of SNALP formulated siRNA, or phosphate-buffered saline by intravenous injection of 10 mL / kg in the lateral tail vein. The siRNA dose administered was 0.025, 0.050 or 0.25 mg / kg body weight. Approximately 48 h after SNALP injection, animals were euthanized and liver tissues were collected in RNA stabilizing solution.

[0412] Organizational Analysis:

[0413]Essentially as described in Judge et al., 2006, Molecular Therapy (Molecular Thera...

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Abstract

The present invention provides compositions comprising therapeutic nucleic acids such as interfering RNA (e.g., dsRNA such as siRNA) that target aldehyde dehydrogenase (ALDH) gene expression, lipid particles comprising one or more (e.g., a cocktail) of the therapeutic nucleic acids, methods of making the lipid particles, and methods of delivering and / or administering the lipid particles (e.g., for treating alcoholism in humans).

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 599,238, filed February 15, 2012, and U.S. Provisional Patent Application No. 61 / 543,700, filed October 5, 2011, under 35 U.S.C. $119(e), by All citations of them are incorporated herein by their contents. [0003] Notes on Sequence Listing [0004] The Sequence Listing pertaining to this application is provided in text format in lieu of a paper version, and is hereby incorporated by reference into the specification. The name of the text file containing the sequence listing is TEKM_074_02WO_ST25.txt. The text file is 12KB, created on October 4, 2012, and submitted electronically via EFS-Web. Background of the invention [0005] Alcoholism is the addiction or dependence on drinking excessive amounts of alcoholic beverages such as beer, wine and distilled spirits. Alcoholism is also sometimes called alcohol abuse or alcohol dependence. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H21/02C12N15/11
CPCA61K9/127C12Y102/01003C12N2310/14C12N15/1137C07H21/02A61K31/713A61P25/32A61P43/00C12N2310/321C12N2310/3521
Inventor 伊恩·麦克拉克伦埃米·C·H·李
Owner PROTIVA BIOTHERAPEUTICS
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