Adenoviral vectors for treating diseases

Abstract

Adenoviral vectors, including mutant adenoviruses, that have restriction sites in the E3 region, that facilitate its partial or total deletion, or select genes contained therein, and optionally compositions and methods for substituting heterologous gene(s) in the partially or totally deleted E3 region(s), which heterologous gene(s) being operably linked to endogenous adenoviral transcriptional control sequences will exhibit an expression pattern, both in terms of timing and degree of expression, similar to the endogenous adenoviral gene(s) that it replaces, and further optionally including mutations in other parts of the adenoviral genome, including certain E1B or E1A regions, and that have applications for diagnosing or treating disease, preferably disease involving unwanted cell growth, including cancer.

Description

FIELD OF THE INVENTION [0001] The invention described herein relates generally to the field of gene therapy, and more specifically to adenoviral vectors that have prophylactic or therapeutic applications. BACKGROUND OF THE INVENTION [0002] Adenovirus is a vector of choice for performing gene therapy. See, Jolly, D., Cancer Gene Therapy, vol. 1, no. 1, 1994: pp 51-64. The well-characterized molecular genetics of adenovirus render it an advantageous vector in this regard. Adenoviruses are nonenveloped icosohedral double-stranded DNA viruses with a linear genome of approximately 36 kilobase pairs. Each end of the viral genome has a short sequence known as the inverted terminal repeat (or ITR), which is required for viral replication. Portions of the viral genome can be readily substituted with DNA of foreign origin, and furthermore, recombinant adenoviruses are structurally stable. [0003] The adenovirus replication cycle has two phases: and early phase, during which 4 transcription uni...

AI Technical Summary

Benefits of technology

[0015] A first object of the invention is to describe methods and compositions for treating or preventing cancer wherein said methods and compositions involve administering to a patient in need of treatment a recombinant adenoviral vector which vector has the properties of infecting and replicati...

Problems solved by technology

Human Factor IX levels, however, slowly declined to baseline by nine weeks after injection, and were not re-established by a second vector injection.

The development of neutralizing antibodies to the adenovirus resulted in a second dose being completely ineffective.

The authors further show that cyclosporin A is not effective in blocking the humoral response to the vector.

Such attempted re-injection was unsuccessful.

When these adenoviruses are administered to an animal host, cells harboring the recombinant viral genome express the heterologous gene as desired; however, low level expression of viral genes also occurs.

There are, however, several limitations to adenovirus gene transfer which are due in part to host responses directed at either the adenovirus vector particle, breakdown products of the vector particle, or the transduced cells.

Recent studies in cotton rats, however, have demonstrated that host immune responses directed towards adenoviral vectors correlate with decreased efficiency of gene transfer and expression after repeated administration.

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