Inhibitors of DNA immunostimulatory sequence activity

Abstract

The invention consists of oligonucleotides which inhibit the immunostimulatory activity of ISS-ODN (immunostimulatory sequence oligodeoxynucleotides) as well as methods for their identification and use. The oligonucleotides of the invention are useful in controlling therapeutically intended ISS-ODN adjuvant activity as well as undesired ISS-ODN activity exerted by recombinant expression vectors, such as those used for gene therapy and gene immunization. The oligonucleotides of the invention also have anti-inflammatory activity useful in reducing inflammation in response to infection of a host with ISS-ODN containing microbes, in controlling autoimmune disease and in boosting host Th2 type immune responses to an antigen. The invention also encompasses pharmaecutically useful conjugates of the oligonucleotides of the invention (including conjugate partners such as antigens and antibodies).

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 048,794 filed on Jun. 6, 1997, which is incorporated herein by reference.BACKGROUND FOR THE INVENTION[0002] 1. Field of the Invention[0003] The invention relates to immunostimulatory sequences in DNA. The invention further relates to recombinant expression vectors for use in gene therapy.[0004] 2. History of the Related Art[0005] Recombinant expression vectors are the tools which researchers and clinicians use to achieve the goals of gene therapy and gene immunization. In gene therapy, viral and non-viral vectors are used to deliver an expressible gene into a host to replace a missing or defective gene, or to otherwise supply the host with a therapeutically beneficial polypeptide. In gene immunization, mostly non-viral vectors are used to induce an immune response by the host to an expressed antigen.[0006] One of the obstacles to successful clinical practice of both gene therapy and gene immunization h...

AI Technical Summary

Benefits of technology

[0010] The compounds of the invention are also useful in modulating the immunostimulatory activity of ISS-ODN administered as adjuvants to boost host immune responses to antigen in, for example, immunotherapy. In this respect, the compounds of the invention permit exquisite control over the effect of ISS-ODN based adjuvants in a host.

[0011] Further, the compounds of the invention reduce host inflammation generated in response to an infection by an ISS-ODN containing bacteria or virus. Advantageously, the compounds of the invention can be administered to inhibit ISS-ODN activity exerted by a microbe even if the identity of the particular ISS-ODN present in the microbe is unknown. Thus, the compounds of the invention can be considered to be broad spectrum anti-inflammatory agents.

[0018] Thus, in another aspect, the invention provides a simple and effective alternative to the arduous task of eliminating ISS-ODN activity from recombinant expression vectors by identifying all ISS-ODN present in the vector and removing them.

Problems solved by technology

One of the obstacles to successful clinical practice of both gene therapy and gene immunization has been the often transient nature of the gene expression achieved in vivo.

However, in a gene therapy protocol, premature loss of gene expression deprives the host of the potential benefits of the therapy (Friedmann, Scientific American, "Making Gene Therapy Work" (June 1997)).

However, plasmids and cosmids are subject to degradation in vivo more quickly than viruses and therefore may not deliver an adequate dosage of IIS-ON to substantially inhibit ISS-ODN immunostimulatory activity exerted by a systemically administered gene therapy vector.

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