Method for opening tight junctions

Abstract

The use of antagonists to JAM-1 Claudin-4 and occludin to open tight junctions. The antagonists include, by way of example antibodies and antibody fragments that bind to the proteins and small interfering nucleic acids that downregulate the mRNA encoding the proteins.

Description

[0001] This claims the benefit under 35 U.S.C. § 119 (e) of U.S. Provisional Patent Application Ser. No. 60 / 529,682 filed on Dec. 15, 2003 the entire contents of which is incorporated by reference.BACKGROUND OF THE INVENTION [0002] The teachings of all of the references cited herein are incorporated in their entirety by reference. [0003] A major disadvantage of drug administration by injection is that trained personnel are often required to administer the drug. For self-administered drugs, many patients are reluctant or unable to give themselves injections on a regular basis. Injection is also associated with increased risks of infection. Other disadvantages of drug injection include variability of delivery results between individuals, as well as unpredictable intensity and duration of drug action. [0004] Despite these noted disadvantages, injection remains the only approved delivery mode for a many important therapeutic compounds. These include conventional drugs, as well as a rapi...

AI Technical Summary

Benefits of technology

[0009] In relation to these needs, an especially challenging need persists in the art for methods and compositions to enhance mucosal delivery of biotherapeutic compounds that will overcome mucosal epithelial barrier mechanisms. Selective permeability of mucosal epithelia has heretofore presented major obstacles to mucosal delivery of therapeutic macromolecules, including biologically active peptides and proteins. Accordingly, there remains a substantial unmet need in the art for new methods and tools to facilitate mucosal delivery of biotherapeutic compounds. In particular, there is a compelling need in the art for new methods and formulations to facilitate mucosal delivery of biotherapeutic compounds that have heretofore proven refractory to delivery across mucosal barriers.

Problems solved by technology

A major disadvantage of drug administration by injection is that trained personnel are often required to administer the drug.

For self-administered drugs, many patients are reluctant or unable to give themselves injections on a regular basis.

Injection is also associated with increased risks of infection.

Other disadvantages of drug injection include variability of delivery results between individuals, as well as unpredictable intensity and duration of drug action.

Delivery of these compounds via alternate routes of administration, for example, oral, nasal and other mucosal routes, often yields variable results and adverse side effects, and fails to provide suitable bio-availability.

For macromolecular species in particular, especially peptide and protein therapeutics, alternate routes of administration are limited by susceptibility to inactivation and poor absorption across mucosal barriers.

However, mucosal delivery of biologically active agents is limited by mucosal barrier functions and other factors.

Other therapeutic compounds, including large molecule drugs, peptides and proteins, are often refractory to mucosal delivery.

Peptides and proteins are poorly lipid soluble, and hence exhibit poor absorption characteristics across mucosal surfaces.

In addition to their poor intrinsic permeability, large macromolecular drugs, including proteins and peptides, are often subject to limited diffusion, as well as lumenal and cellular enzymatic degradation and rapid clearance at mucosal sites.

Mucosal tissues provide a substantial barrier to the free diffusion of macromolecules, while enzymatic activities present in mucosal secretions can severely limit the bioavailability of therapeutic agents, particularly peptides and proteins.

At certain mucosal sites, such as the nasal mucosa, the typical residence time of proteins and other macromolecular species delivered is limited, e.g., to about 15-30 minutes or less, due to rapid mucociliary clearance.

In summary, previous attempts to successfully deliver therapeutic compounds, including small molecule drugs and protein therapeutics, via mucosal routes have suffered from a number of important and confounding deficiencies.

In relation to these needs, an especially challenging need persists in the art for methods and compositions to enhance mucosal delivery of biotherapeutic compounds that will overcome mucosal epithelial barrier mechanisms.

Selective permeability of mucosal epithelia has heretofore presented major obstacles to mucosal delivery of therapeutic macromolecules, including biologically active peptides and proteins.

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