Marina Biotech, Inc.

Genevant Sciences Gmbh

Arcturus Therapeutics, Inc.

Nastech Pharmaceutical Company, Inc.

Phaserx, Inc.

Michael E Houston, Jr

Mary Gallagher Prieve

Pierrot Harvie

Steven C Quay

Roger C Adami

Kathy L Fosnaugh

Shaguna Seth

Renata Fam

Sean D Monahan

Charbel Diab

Maher Qabar

Anna Galperin

Michael S DeClue

Debashish Roy

Amber E Paschal

Russell N Johnson

Paul Hickok Johnson

Richard E Herman

Narendra Vaish

Kunyuan Cui

Douglas L Badders

Lishan Chen

Michael V Templin

Rachel E Johns

Tracy Matray

Yuching Chen

Mohammad Ahmadian

Shu-Chih Chen

Sasha J Mayer

Barry A Polisky

Iwona M Maciagiewicz

Shu-Chih Chen Quay

Jaya S Giyanani

Disclosed are methods for delivering a therapeutic or diagnostic agent to the cytosol of a cell in a subject. The disclosed methods generally include administering to the subject an effective amount of a lipid nanoparticle comprising the therapeutic or diagnostic agent and an effective amount of a membrane-destabilizing polymer. Also disclosed are related compositions and delivery systems.

Methods, compositions, and systems for delivering therapeutic and diagnostic agents into cells

Described herein are block copolymers, and methods of making and utilizing such copolymers. The described block copolymers are disruptive of a cellular membrane, including an extracellular membrane, an intracellular membrane, a vesicle, an organelle, an endosome, a liposome, or a red blood cell. Preferably, in certain instances, the block copolymer disrupts the membrane and enters the intracellular environment. In specific examples, the block copolymer is endosomolytic and capable of delivering an oligonucleotide (e.g., an mRNA) to a cell. Compositions comprising a block copolymer and an oligonucleotide (e.g., an mRNA) are also disclosed.

Nucleic acid constructs and methods of using the same

Block copolymers

This invention provides single-stranded and multi-stranded compounds that are useful in various therapeutic modalities to regulate the expression of nucleic acid molecules in a cell. A range of compounds is provided, each containing one or more conformationally restricted nucleomonomers (CRN). In addition, compounds can contain one or more conformationally restricted nucleomonomers and one or more hydroxymethyl substituted nucleomonomers (unlocked nucleomonomers, UNA).

Therapeutics with conformationally restricted monomers

Lipopeptide compounds having a central peptide HHHHHKHHHKKKHKHKKK (SEQ ID NO:15) and a lipophilic group attached to each terminus of the peptide, and salts thereof. The lipopeptides are useful for forming pharmaceutical compositions for delivery of nucleic acid agents, such as siRNA and mdRNA agents, as well as in methods for treating the signs and symptoms of disease.

Lipopeptides for delivery of nucleic acids

Processes for synthesis of conformationally restricted nucleomonomers (CRN) by ozonolysis or oxidation of a 2'-vinyl substituted nucleoside precursor with protected 3&#x2032;-hydroxyl, 4&#x2032;-hydroxymethyl and 5&#x2032;-hydroxyl positions. The CRN nucleomonomers can be used to prepare nucleic acid compounds. CRN nucleomonomers for nucleic acid compounds can be prepared in high yields and in multi-gram scale. The nucleic acid compounds can be of various regulatory classes such as antisense RNA for therapeutic modalities useful for treating or preventing diseases or disorders by up- or down-regulating the expression of genes and other nucleic acid based regulatory systems in a cell.

Synthesis and uses of nucleic acid compounds with conformationally restricted monomers

This disclosure provides a range of tyrosine amino acid lipid compounds and compositions useful for drug delivery, therapeutics, and the diagnosis and treatment of diseases and conditions. The amino acid lipid compounds and compositions can be used for delivery of various agents such as nucleic acid therapeutics to cells, tissues, organs, and subjects.

Tyrosine-based lipids for delivery of therapeutics

This disclosure provides a range of amino acid lipid compounds and compositions useful for drug delivery, therapeutics, and the diagnosis and treatment of diseases and conditions. The amino acid lipid compounds and compositions can be used for delivery of various agents such as nucleic acid therapeutics to cells, tissues, organs, and subjects.

Arginine-based lipids for delivery of therapeutics

This disclosure provides double-stranded RNA complexes having one or more hydroxymethyl substituted nucleomonomer(s) in the passenger strand (or sense strand) of an RNA complex. RNA complexes of the disclosure may be useful for therapeutic applications, diagnostic applications or research applications. RNA complexes include short interfering RNA complexes (siRNA) capable of modulating gene expression comprising an antisense strand and a continuous or a discontinuous passenger strand ('sense strand'). Further, one or more hydroxymethyl substituted nucleomonomer(s) of this disclosure may be positioned at the 3'-end, at the 5&#x2032;-end, at both the 3&#x2032;-end and 5&#x2032;end.

UNA oligomer structures for therapeutic agents

Lipopeptide compounds with a central peptide and having lipophilic groups attached at each terminus, and salts and uses thereof. The lipophilic groups can be derived from a naturally-occurring lipid, or can be a C(1-22)alkyl, C(6-12)cycloalkyl, C(6-12)cycloalkyl-alkyl, C(3-18)alkenyl, C(3-18)alkynyl, C(1-5)alkoxy-C(1-5)alkyl, or a sphinganine, or (2R,3R)-2-amino-1,3-octadecanediol, icosasphinganine, sphingosine, phytosphingosine, cis-4-sphingenine. The compounds can be used in compositions to deliver active agents to cells, including interfering-RNA agents and antisense RNAs.

A delivery-enhancing peptide comprising the amino acid sequence of SEQ ID NO:11 or salt thereof. This invention is directed towards methods and compositions to administer a double-stranded ribonucleic acid to a mammal so as to effectuate transfection of the double-stranded RNA into a desired tissue of the mammal.

Methods and compositions for enhancing delivery of double-stranded RNA or a double-stranded hybrid nucleic acid to regulate gene expression in mammalian cells

Amino acid lipids and uses thereof

Polynucleotide delivery-enhancing polypeptides are admixed or complexed with, or conjugated to, nucleic acids for enhancing delivery the nucleic acids into cells. The transported nucleic acids are active in target cells as small inhibitory nucleic acids (siNAs) that modulate expression of target genes, mediated at least in part by RNA interference (RNAi). The siNA/polypeptide compositions and methods of the invention provide effective tools to modulate gene expression and alter phenotype in mammalian cells, including by altering phenotype in a manner that eliminates disease symptoms or alters disease potential in targeted cells or subject individuals to which the siNA/polypeptide compositions are administered.

Compositions and methods for enhancing delivery of nucleic acids into cells and for modifying expression of target genes in cells

Growing community of inventors

Sammamish, WA, United States of America

Michael E Houston, Jr