University of British Columbia

Inex Pharmaceuticals Corporation

The Liposome Company, Inc.

Tekmira Pharmaceuticals Corporation

Other

Arbutus Biopharma Corporation

Acuitas Therapeutics, Inc.

The Lipsome Company, Inc.

Alnylam Pharmaceuticals, Inc.

Mayer, Lawrence D.

Bally, Marcel B.

Madden, Thomas D.

Cullis, Pieter R.

Hope, Michael J.

Fountain, Michael W.

Michael J Hope

Pieter Rutter Cullis

Thomas D Madden

Steven Michial Ansell

Muthiah Manoharan

Kallanthottathil G Rajeev

Martin A Maier

Andrew S Janoff

Muthusamy Jayaraman

Akin Akinc

Marcel B Bally

Peter Scherrer

Sean C Semple

Jeffery J Wheeler

Yuan-Peng Zhang

Dorothy L Reimer

Sandra K Klimuk

Troy Harasym

Michael W Fountain

Richard S Ginsberg

Dan Debeyer

Regina L Jablonski

Hugh P Schieren

Wendi Rodrigueza

Lawrence D Mayer

Kim F Wong

Barbara Mui

Jianxin Chen

Pieter R Cullis

Marco A Ciufolini

Norbert Maurer

David B Fenske

Barbara Low Shoud Mui

Xinyao Du

Kevin Jon Williams

Colin P Tilcock

Jeffrey Jerome Wheeler

Christopher James Barbosa

Barbara L S Mui

Ellen K Wasan

Quet Fah Ahkong

Deirdre McIntosh

Nancy Dos Santos

Paulo Jia Ching Lin

Barbara Ls Mui

Colin Ps Tilcock

Huge P Schieren

Fountain Michael W

Srinivasulu Masuna

Masunu Srinivasulu

Ismail Mahmoud Hafez

Marco A Cuifolini

Improved formulations of lipid nanoparticles are provided. Use of the lipid nanoparticles for delivery of a therapeutic agent and methods for their preparation are also provided.

Lipid nanoparticle formulations

The present invention provides superior compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target proteins at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.

Amino lipids and methods for the delivery of nucleic acids

Methods for the preparation of a lipid-nucleic acid composition are provided. According to the methods, a mixture of lipids containing a protonatable or deprotonatable lipid, for example an amino lipid and a lipid such as a PEG- or Polyamide oligomer-modified lipid is combined with a buffered aqueous solution of a charged therapeutic agent, for example polyanionic nucleic acids, to produce particles in which the therapeutic agent is encapsulated in a lipid vesicle. Surface charges on the lipid particles are at least partially neutralized to provide surface-neutralized lipid-encapsulated compositions of the therapeutic agents. The method permits the preparation of compositions with high ratios of therapeutic agent to lipid and with encapsulation efficiencies in excess of 50%.

Lipid-encapsulated polyanionic nucleic acid

The present invention includes novel liposomes comprising dihydrosphingomyelin. The invention also includes compositions comprising these liposomes and a therapeutic agent, in addition to methods and kits for delivering a therapeutic agent or treating a disease, e.g., a cancer, using these compositions.

Liposomal formulations comprising dihydrosphingomyelin and methods of use thereof

Novel lipid-nucleic acid particulate complexes which are useful for in vitro or in vivo gene transfer are described. The particles can be formed using either detergent dialysis methods or methods which utilize organic solvents. Upon removal of a solubilizing component (i.e., detergent or an organic solvent) the lipid-nucleic acid complexes form particles wherein the nucleic acid is serum-stable and is protected from degradation. The particles thus formed have access to extravascular sites and target cell populations and are suitable for the therapeutic delivery of nucleic acids.

Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer

The present invention provides compositions and methods for treating atherosclerosis. The compositions comprise unilamellar liposomes having an average diameter of 100-150 nanometers. Methods for treating atherosclerosis employing the compositions of the present invention are also provided.

Liposome compositions and methods for the treatment of atherosclerosis

Particle aggregation of lipid:nucleic acid complex particles is prevented by incorporating a non-cationic lipid into lipid:nucleic acid complex particles containing a cationic lipid and a nucleic acid polymer. The non-cationic lipid is a polyethylene glycol-based polymer.

Method of preventing aggregation of a lipid:nucleic acid complex

Lipidic compositions with superior characteristics for in vivo delivery of oligodeoxynucleotides (ODN) can easily and efficiently be made in the form of small multilamellar vesicles. The compositions contain a population of nucleic acid-containing lipid vesicles in a liquid carrier, and at least a portion of the lipid vesicles are small multilamellar vesicles. The small multilamellar vesicles are made from a lipid component including 20-30 mol % of an ionizable amino lipid such as DODAP, and a steric barrier lipid such as PEG-CerC ; and an oligodeoxynucleotide contained in the lumen or interlamellar spaces of the small multilamellar vesicles. The ODN and lipid components are preferably present in the small multilamellar vesicles in a mole ratio of from 0.15 to 0.25. The compositions of the invention can be made by preparing two solutions: a lipid mixture with 20-30 mol % of the ionizable amino lipid, the steric barrier lipid and additional lipid components selected from among neutral lipids and sterols in an ethanolic solvent; and a solution of oligodeoxynucleotide in an aqueous solvent having a pH at which the ionizable amino lipid is positively charged. The lipid mixture is added to the solution of oligodeoxynucleotide to form a mixture containing lipid vesicles which is then massed through a filter to produce sized lipid vesicles in a solution containing ethanol. The ethanol is then removed, for example by dialysis. Then, the pH of the solution surrounding the sized lipid vesicles is increased to reduce the net positive charge on the exterior of the sized lipid vesicles.

Composition containing small multilamellar oligodeoxynucleotide-containing lipid vesicles

Plasmid-lipid particles which are useful for transfection of cells in vitro or in vivo are described. The particles can be formed using either detergent dialysis methods or methods which utilize organic solvents. The particles are typically 65-85 nm, fully encapsulate the plasmid and are serum-stable.

Methods for encapsulating plasmids in lipid bilayers

The present invention provides a liposomal composition for treating dislipidemias in human subjects, a method of using a liposomal composition, and devices and modes of operation of the devices and of the compositions, and kits related thereto. The invention provides for the reverse transport of cholesterol from peripheral tissues to the liver in a warm blood mammal while controlling plasma atherogenic lipoprotein concentrations, including LDL concentrations. A method described above and mode of operation of the devices includes the stop of administering an effective amount of a multiplicity of acceptors comprised of phospholipids substantially free of sterol. A method described above optionally includes the stop of periodically assaying atherogenic lipoprotein concentrations with an assay during the treatment period to assess atherogenic lipoprotein concentrations and obtain an atherogenic lipoprotein profile.

Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias

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Vancouver, Canada

Michael J Hope