Isis Pharmaceuticals, Inc.

Ionis Pharmaceuticals, Inc.

Lonis Pharmaceuticals, Inc.

Michael T Migawa

Eric E Swayze

Punit P Seth

Richard Holmes Griffey

Thazha P Prakash

Michael Oestergaard

Xiaojing Wang

W Brad Wan

Stanley T Crooke

Stephen Hanessian

Xue-hai Liang

Susanta Sekhar Adhikari

Janek Szychowski

Kandasamy Pachamuthu

Balkrishen Bhat

Wen Shen

Guillermo Vasquez

Charles Allerson

Bruce S Ross

Quanlai Song

Mingming Han

Garth A Kinberger

Tadeusz Krzysztof Wyrzykiewicz

Jinghua Yu

Walter F Lima

Hongjiang Wu

Jie Xia

Isaiah E Cedillo

Dana Chreng

Sayten P Patel

Satyen P Patel

Joshua Nichols

William John Drury, Iii

Brooke A Anderson

The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.

Modified compounds and uses thereof

The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one modified internucleoside linking group.

Linkage modified oligomeric compounds and uses thereof

Provided herein are improved methods for the synthesis of reactive conjugate clusters and intermediates used in such methods. In particular, improvements are provided that enhance the synthesis of reactive conjugate clusters by reducing the number of synthetic steps required. The reactive conjugate clusters prepared using the improved methods don't include any transacylation impurities that are formed using existing methods. The improved methods also provide an increase in overall yield and a cost benefit over existing methods.

Method for synthesis of reactive conjugate clusters

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the gomeric compounds are conjugated to N-Acetylgalactosamine or to N-Acetylgalactosamine analogues.

Conjugated antisense compounds and their use

Provided herein are methods for removal of monomethoxytrityl groups from oligomeric compounds comprising terminally linked monomethoxytrityl protected amino groups. The present methods differ from standard methods for 5'-dimethoxytrityl removal from oligonucleotides in that the present methods are performed at elevated temperatures and higher pH. In certain embodiments, the present methods provide detritylated oligomeric compounds having a reduced percentage of depurination relative to the same detritylated oligomeric compounds prepared using standard methods. In certain embodiments, the present methods provide an increased rate of detritylation compared to standard methods. In certain embodiments, the modification of the final detritylation step results in an improved yield.

Method for solution phase detritylation of oligomeric compounds

The present invention provides oligomeric compounds comprising at least one neutral methoxypropyl phosphonate modified internucleoside linkage. Such oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Such oligomeric compounds have enhanced stability to exposure to base during synthesis. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

Linkage modified oligomeric compounds

Provided herein are methods for the synthesis of oligomeric compounds wherein the standard coupling protocols are modified when coupling bicyclic nucleosides of Formula I. More particularly, the modified coupling protocols provide for a decrease in the ratio of phosphoramidite solution to activator solution in the coupling reagent with an increased contact time. The modified coupling protocols provide for oligomeric compounds having comparable yields to similar oligomeric compounds having modified nucleosides other than bicyclic nucleosides of Formula I.

Method of preparing oligomeric compounds using modified coupling protocols

Provided herein are novel 5'-(S)&#x2014;CHsubstituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, the furanose ring of each of the novel 5&#x2032;-(S)&#x2014;CHsubstituted bicyclic nucleosides includes a 2&#x2032; to 4&#x2032; bridging group. The 5&#x2032;-(S)&#x2014;CHsubstituted bicyclic nucleosides are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as for example increasing the binding affinity. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

5'-substituted bicyclic nucleosides and oligomeric compounds prepared therefrom

The present invention provides bicyclic cyclohexose nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.

Bicyclic cyclohexose nucleic acid analogs

The present invention provides compositions and methods for the optimization of cleavage of RNA species by RNase H. In some embodiments, the invention provides oligonucleotides that possess two or more regions of differing conformation, and at least one transitional nucleobase positioned between the regions that is capable of modulating transfer of the helical conformation characteristic of the region bound to the 3'hydroxy thereof, to the region bound to the 5&#x2032; hydroxyl thereof.

Compositions and methods for optimizing cleavage of RNA by RNase H

The present invention is directed to analogs of aminoglycoside compounds as well as their preparation and use as prophylactic or therapeutics against microbial infection.

Antibacterial 4,6-substituted 6', 6&#x2033; and 1 modified aminoglycoside analogs

Growing community of inventors

Carlsbad, CA, United States of America

Michael T Migawa