Genzyme Corporation

University of Iowa Research Foundation

Ronald K Scheule

Seng H Cheng

John Marshall

Simon J Eastman

Craig S Siegel

David J Harris

Edward R Lee

Nelson S Yew

Shirley C Hubbard

Mathieu B Lane

Chau-Dung Chang

Rebecca G Bagley

Andrew Charles Good

Bradford Hirth

Yibin Xiang

Cassandra Celatka

Markus Metz

Zhong Zhao

Timothy E Weeden

Carol A Nelson

Elyse Bourque

Thomas A Natoli

Hongmei Zhao

Bruce M Wentworth

Elina Makino

Nicholas P Clayton

Oxana Beskrovnaya

Eric A Rowe

S Catherine Hubbard

Mario A Cabrera-Salazar

Katherine Jancsics

Herve Husson

H Michael Shepard

Michael J Welsh

Renato Skerlj

Richard J Gregory

John P Leonard

Daniel C Maneval

Renato Tony Skerlj

Allen J Fasbender

Duane E Johnson

John Leonard

Jennifer D Tousignant

Quiming Chu

Andrew Good

Thomas Natoli

Katherine Jancisics

Malgorzata Przybylska

The invention relates to inhibitors of glucosylceramide synthase (GCS) of the Formula I: represented by the following structural formula or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein, useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treatment of cancer.

Glucosylceramide synthase inhibitors

The present disclosure relates to antisense oligonucleotides (AONs) for modulating the expression of glycogen synthase. AONs of the present disclosure may be useful in treating diseases associated with the modulation of the expression of the enzyme glycogen synthase, such as Pompe disease. Also provided by the present disclosure are compositions comprising AONs, as well as methods of down regulating mRNA coding for glycogen synthase, methods for reducing glycogen synthase in skeletal and cardiac muscle, and methods for treating Pompe disease.

Inhibiting or downregulating glycogen synthase by creating premature stop codons using antisense oligonucleotides

The invention relates to inhibitors of glucosylceramide synthase (GCS), such as Compound of Formula I, shown below, as defined herein, useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treatment of cancer. 

The invention provides methods of treating a diabetic subject comprising administering a glucosylceramide synthase inhibitor to the subject.

Method of lowering blood glucose

Methods of treating diabetes mellitus

The well-differentiated airway epithelium is the principal target tissue for gene therapy for the treatment of CF. However, recent studies have shown that gene delivery vehicles, such as cationic lipid:DNA complexes, can be inefficient at binding to and internalizing into polarized epithelial cells. The present invention provides a method to improve gene therapy by using a compound capable of disrupting tight junctions. In the practice of the invention, the transfection of a biologically active molecule by a cationic amphiphile:biologically active molecule complex or other lipid or viral or nonviral vectors is improved by treating the cells with a class of compounds known in the art as absorption enhancers or tight junction disrupting compounds.

Transgene expression in polarized cells

Cationic amphiphiles for intracellular delivery of therapeutic molecules

Novel cationic amphiphiles are provided that facilitate transport of biologically active (therapeutic) molecules into cells. The amphiphiles contain lipophilic groups derived from steroids, from mono or dialkylamines, or from alkyl or acyl groups; and cationic groups, protonatable at physiological pH, derived from amines, alkylamines or polyalkylamines. There are provided also therapeutic compositions prepared typically by contacting a dispersion of one or more cationic amphiphiles with the therapeutic molecules. Therapeutic molecules that can be delivered into cells according to the practice of the invention include DNA, RNA, and polypeptides. Representative uses of the therapeutic compositions of the invention include providing gene therapy, and delivery of antisense polynucleotides or biologically active polypeptides to cells. With respect to therapeutic compositions for gene therapy, the DNA is provided typically in the form of a plasmid for complexing with the cationic amphiphile. Novel and highly effective plasmid constructs are also disclosed, including those that are particularly effective at providing gene therapy for clinical conditions complicated by inflammation. Additionally, targeting of organs for gene therapy by intravenous administration of therapeutic compositions is described.

Organ-specific targeting of cationic amphiphile / DNA complexes for gene therapy

Organ-specific targeting of cationic amphiphile/DNA complexes for gene

Cationic amphiphile/DNA complexes

Novel cationic amphiphiles are provided that facilitate transport of biologically active (therapeutic) molecules into cells. By this invention, such cationic amphiphile is used in a state in which it is capable of accepting additional protons, i.e., it is not fully protonated. For purposes of this invention, cationic amphiphiles may be considered to encompass four general categories: (A) T-shaped/steroid-based amphiphiles; (B) T-shaped/non steroid-based amphiphiles; (C) non T-shaped/steroid based amphiphiles and (D) non T-shaped/non steroid-based amphiphiles.

Cationic amphiphile compositions for intracellular delivery of

Novel compositions are provided. Typically, the compositions comprise one or more neutral co-lipids and also a cationic amphiphile. Therapeutic compositions are prepared according to the practice of the invention by contacting a therapeutically active molecule with a dispersion of neutral co-lipid(s) and amphiphile(s).

Compositions comprising cationic amphiphiles and co-lipids for

Cationic amphiphiles and plasmids for intracellular delivery of

Cationic amphiphiles containing ester or ether-linked lipophilic groups

Growing community of inventors

Hopkinton, MA, United States of America

Ronald K Scheule