Genzyme Corporation

University of Iowa Research Foundation

Mathieu B Lane

Seng H Cheng

David J Harris

Edward R Lee

Craig S Siegel

John Marshall

Ronald K Scheule

Simon J Eastman

Shirley C Hubbard

Nelson S Yew

Eric A Rowe

Michael J Welsh

Canwen Jiang

Chau-Dung Chang

Allen J Fasbender

Cationic amphiphiles for intracellular delivery of therapeutic molecules

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride (Cl,) channel regulated by phosphorylation and intracellular nucleotides. CFTR is the major Cl,transport pathway in airway epithelial cells. The abnormal transepithelial Cl,transport and subsequent defective fluid transport caused by CF is a result of the genetic mutations of the gene coding for the CFTR protein. The present invention is directed to the novel use of ionophores as artificial Cl,transport pathways into CF epithelia to treat the defective Cl,and fluid transport lonophores and in particular, small molecule ionophores, represent a potential novel means of treating CF. The invention also includes using an ionophore to generate chloride secretion on intact monolayers of airway epithelia cells and other epithelia cells by administering an ionophore to a mammal.

Small molecule chloride transport

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

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.

Cationic amphiphiles containing ester or ether-linked lipophilic groups

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 ether or ester-linked alkyl 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.

Cationic amphiphiles containing steroid lipophilic groups for

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Cambridge, MA, United States of America

Mathieu B Lane