The Salk Institute for Biological Studies

Clodagh O'Shea

Colin Powers

William N Partlo

Shigeki Miyake-Stoner

Lei Zhang

Jason DeHart

Michael Lyman

Tumor-selective recombinant adenoviruses that possess deletions or modifications in the E3 region are described. Recombinant adenoviruses that express adenovirus death protein (ADP) but have a deletion of at least three of the remaining six E3 genes exhibit enhanced virus replication. The recombinant adenoviruses further include additional modifications to allow selective replication in tumor cells and to detarget viruses from the liver. Use of the recombinant adenoviruses for cancer treatment is described.

Oncolytic adenovirus with enhanced replication properties comprising modifications in E1A, E3, and E4

Recombinant adenovirus genomes that include an exogenous open reading frame (ORF) and a self-cleaving peptide coding sequence are described. Optimal placement of the exogenous genes for minimal impact on viral kinetics is further disclosed. Therapeutic applications of the recombinant adenoviruses are also described.

Exogenous gene expression in recombinant adenovirus for minimal impact on viral kinetics

Synthetic adenoviruses with liver detargeting mutations and expressing an adenovirus type 34 (Ad34) fiber protein, or a chimeric fiber protein with an Ad34 knob domain, are described. The synthetic adenoviruses traffic to sites of tumors. Use of the synthetic adenoviruses for delivering diagnostic or therapeutic transgenes to tumors are also described.

Tumor-targeting synthetic adenoviruses and uses thereof

Synthetic adenoviruses having chimeric fiber proteins and liver detargeting mutations are described. The synthetic adenovirus vectors are capable of specifically infecting cells at wound sites or in regions of damaged tissue. The synthetic adenovirus vectors also are capable of expressing transgenes, such as wound healing factors, at sites of wounded or damaged tissue. Accordingly, the described vectors can be used to detect wounded or damaged tissue, and/or to promote wound healing and regeneration of damaged tissue, such as by expression of heterologous wound healing or tissue regeneration factors.

Synthetic adenoviruses with tropism to damaged tissue for use in promoting wound repair and tissue regeneration

Recombinant adenovirus genomes that include a heterologous open reading frame (ORF) and a self-cleaving peptide coding sequence are described. The recombinant adenovirus genomes and recombinant adenoviruses produced by the disclosed genomes can be used, for example, in high-throughput assays to measure virus replication kinetics. Methods for measuring replication kinetics of a recombinant adenovirus are also described.

High throughput assay for measuring adenovirus replication kinetics

An adenovirus comprising an E1A polypeptide comprising one or more modifications and comprising an E4orf6/7 polypeptide comprising one or more modifications is described. Compositions and kits comprising the modified adenoviruses are also described. Further described is a method of treating a proliferative disorder in a subject comprising administering to the subject an adenovirus comprising the E1A polypeptide comprising one or more modifications and comprising the E4orf6/7 polypeptide comprising one or more modifications.

Oncolytic adenovirus compositions

Recombinant herpes simplex virus (HSV)-1 capable of selectively replicating in alternative lengthening of telomeres (ALT)-dependent tumor cells are described. The recombinant HSV-1 are ICP0-deficient, such as by complete deletion of the ICP0 gene, or mutation of the ICP0 gene sufficient to diminish or eliminate E3 ubiquitin ligase activity of ICP0. In some cases, the recombinant HSV-1 further include additional gene deletions or mutations, such as those that render the virus glycoprotein C (gC) deficient, or include a heterologous gene, such as a gene encoding an immunostimulatory molecule. Methods of treating ALT-dependent cancer, and methods of selectively killing ALT-dependent tumor cells are also described.

HSV-1 oncolytic virus therapies that specifically kill ALT dependent cancers

Exogenous gene expression in therapeutic adenovirus for minimal impact on viral kinetics

Methods of assembling modified adenoviruses, libraries of adenoviral gene modules and compositions thereof are provided herein.

Adenoviral assembly method

Compositions and methods for retargeting adenovirus to a cell using chemical dimers are described. In particular, a recombinant adenovirus comprising a nucleic acid comprising a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate is provided.

Selective cell targeting using adenovirus and chemical dimers

Compositions and methods for detecting a cancer in a subject using a recombinant reporter adenovirus are described. In particular, recombinant adenovirus is used to diagnose a cancer in a patient and further used for screening compounds effective in treating the cancer in said patient.

Adenoviral tumor diagnostics

Anti-cancer adenoviruses, methods of use and methods of making the same are provided herein.

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San Diego, CA, United States of America

Clodagh O'Shea