Isis Pharmaceuticals, Inc.

Other

Baylor College of Medicine

Novartis Corporation

Clarence Frank Bennett

Muthiah Manoharan

Phillip Dan Cook

David J Ecker

Russell M Medford

Edgardo Baracchini, Jr

Brett P Monia

Balkrishen Bhat

Stanley T Crooke

Nicholas M Dean

Karl-Heinz Altmann

Christopher K Mirabelli

Doriano Fabbro

Normand Hebert

Harris Busch

Rose K Busch

Thomas Geiger

Yasuo Saijo

Laszlo Perlaky

Marcel Muller

The present invention relates to compositions and methods for the pulmonary delivery of nucleic acids, particularly oligonucleotides. In one preferred embodiment, the compositions and methods of the invention are utilized to effect the pulmonary delivery of an antisense oligonucleotide to an animal in order to modulate the expression of a gene in the animal for investigative, therapeutic or prophylactic purposes.

Composition and methods for the pulmonary delivery of nucleic acids

Linked nucleosides having at least one functionalized nucleoside that bears a substituent such as a steroid molecule, a reporter molecule, a non-aromatic lipophilic molecule, a reporter enzyme, a peptide, a protein, a water soluble vitamin, a lipid soluble vitamin, an RNA cleaving complex, a metal chelator, a porphyrin, an alkylator, a pyrene, a hybrid photonuclease/intercalator, or an aryl azide photo-crosslinking agent exhibit increased cellular uptake and other properties. The substituent can be attached at the 2'-position of the functionalized nucleoside via a linking group. If at least a portion of the remaining liked nucleosides are 2&#x2032;-deoxy-2&#x2032;-fluoro, 2&#x2032;-O-methoxy, 2&#x2032;-O-ethoxy, 2&#x2032;-O-propoxy, 2&#x2032;-O-aminoalkoxy or 2&#x2032;-O-allyloxy nucleosides, the substituent can be attached via a linking group at any of the 3&#x2032; or the 5&#x2032; positions of the nucleoside or on the heterocyclic base of the nucleoside or on the inter-nucleotide linkage linking the nucleoside to an adjacent nucleoside.

Derivatized oligonucleotides having improved uptake and other properties

Linked nucleosides having at least one functionalized nucleosid that bears a substituent such as a steroid molecule, a reporter molecule, a non-aromatic lipophilic molecule, a reporter enzyme, a peptide, a protein, a water soluble vitamin, lipid soluble vitamin, an RNA cleaving complex, a metal chelator, a porphyrin, an alkylator, a pyrene, a hybrid photonuclease/intercalator, or an aryl azide photo-crosslinking agent exhibit increased cellular uptake and other properties. The substituent can be attached at the 2'-position of the functionalized nucleoside via a linking group. If at least a portion of the remaining linked nucleosides are 2&#x2032;-deoxy-2&#x2032;-fluoro, 2&#x2032;-O-methoxy, 2&#x2032;-O-ethoxy, 2&#x2032;-O-propoxy, 2&#x2032;-O-aminoalkoxy or 2&#x2032;-O-allyloxy nucleosides, the substituent can be attached via a linking group at any of the 3&#x2032; or the 5&#x2032; positions of the nucleoside or on the heterocyclic base of the nucleoside or on the inter-nucleotide linkage linking the nucleoside to an adjacent nucleoside.

Linked nucleosides having at least one functionalized nucleoside that bears a substituent such as a steroid molecule, a reporter molecule, a non-aromatic lipophilic molecule, a reporter enzyme, a peptide, a protein, a water soluble vitamin, a lipid soluble vitamin, an RNA cleaving complex, a metal chelator, a porphyrin, an alkylator, a pyrene, a hybrid photonuclease/intercalator, or an aryl azide photo-crosslinking agent exhibit increased cellular uptake and other properties. The substituent can be attached at the 2&prime;-position of the functionalized nucleoside via a linking group. If at least a portion of the remaining liked nucleosides are 2&prime;-deoxy-2&prime;-fluoro, 2&prime;-O-methoxy, 2&prime;-O-ethoxy, 2&prime;-O-propoxy, 2&prime;-O-aminoalkoxy or 2&prime;-O-allyloxy nucleosides, the substituent can be attached via a linking group at any of the 3&prime; or the 5&prime; positions of the nucleoside or on the heterocyclic base of the nucleoside or on the inter-nucleotide linkage linking the nucleoside to an adjacent nucleoside.

The invention is directed to oligonucleotides and oligonucleosides functionalized to include lipophilic moieties and having improved biostability and altered biodistribution in mammals. In one embodiment, such lipophilic oligonucleotide conjugates are used in a method of targeting antisense oligonucleotides to hepatic tissues and thereby preferentially modulating gene expression in the liver and associated tissues of a mammal.

Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals

Genes coding for vascular cell adhesion molecules, particularly VCAM-1, are modulated through interaction of oligonucleotides with transcriptional regulatory factors which bind to the genes. Specific and effective oligonucleotides are provided which interact with the transcriptional regulatory factors to diminish their interaction with the genes and downregulate their function. Multi-modal oligonucleotides are also provided which interact both with a transcriptional regulatory factor and with another aspect of gene function.

Chimeric oligonucleotides for modulating gene expression

Modulation of vascular cell adhesive molecule expression through oligonucleotide interactions

The present invention provides improved methods for tracking the biodistribution of macromolecules and carriers in cells. In accordance with one embodiment, oligonucleotides and lipid carriers are differentially fluorescently labeled and coadministered to the cells. Useful compounds and synthetic methods are also provided.

Methods and compounds for tracking the biodistribution of macromolecule-carrier combinations

Certain oligonucleotides capable of inhibiting the production of p120, a cell proliferation-associated nucleolar protein, are provided. Oligonucleotides designed to be hybridizable with nucleic acids encoding nucleolar proteins are believed to be therapeutically useful. Certain of such oligonucleotides, hybridizable to MRNA encoding p120, were made and found to inhibit the synthesis of p120. The oligonucleotides of the invention are useful for the treatment of diseases characterized by hyperproliferation of cells. Methods of treatment and diagnosis of such diseases using these oligonucleotides are also provided.

Oligonucleotide inhibition of P120

Oligonucleotide modulation of multidrug resistance-associated protein

The invention relates to combinations of PKC-targeted (especially PKC-.alpha.-targeted) deoxyribo- and ribo-oligonucleotides and derivatives thereof with other chemotherapeutic compounds, as well as to pharmaceutical preparations and/or therapies, in relation to disease states which respond to such oligonucleotides or oligonucleotide derivatives, especially to to modulation of the activity of a regulatory protein. In particular, the invention relates to products or combinations comprising antisense oligonucleotides or oligonucleotide derivatives targeted to nucleic acids encoding human PKC and other (preferably standard) chemotherapeutics, either in fixed combination or for chronologically staggered or simultaneous administration, and the combined use of both classes of compounds, either in fixed combination or for chronologically staggered or simultaneous administration, for the treatment of proliferative diseases, especially tumor diseases, that can be treated by inhibition of PKC activity, that is, where the antisense oligonucleotides or oligonucleotide derivatives are targeted to nucleic acids encoding the regulatory protein PKC or active mutated derivatives thereof.

Growing community of inventors

Carlsbad, CA, United States of America

Clarence Frank Bennett