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Modular Adenovirus Assembly Platform

Custom, rapid and systematic assembly of recombinant adenoviral genomes from modular parts.

INVENTION: Although adenoviral vectors are regularly used for the delivery of exogenous DNA to mammalian cells for basic science research, vaccines and gene therapy, the potential of adenoviral vectors in several applications has been greatly hindered by the inability to manipulate the 36kb viral genome rapidly and systematically. In addition, the adenoviral vectors currently in use are generally limited to 2 adenovirus (Ad) serotypes 2 and 5, which restrict infection to cells expressing the CAR receptor. Furthermore, pre-existing neutralizing antibodies against Ad2/5, off-target liver uptake and inflammation greatly limit systemic applications. Researchers at the Salk Institute have developed a novel platform for the rapid assembly of adenoviral vectors from libraries of component parts. The functions and diversity of the genomic parts is provided by previously reported mutations, directed evolution approaches based on structure, heterologous elements and disparate adenovirus serotypes, mutants and species. This assembly method allows for the generation of custom adenoviral vectors in a matter of hours with the desired target specificity, lytic properties and the ability to escape the immune system. 

There are hundreds of adenoviruses, each with unique and specialized capabilities allowing for the infection and replication in different host environments. Adenovirus genomes have a natural modular structure that can be exploited for synthetic biology. The adenoviral genome is divided into 4 modules based on evolutionary conserved sequences and functions. Different combinations of these modules derived from both synthetic and natural sources can be combined using multi-site in vitro recombination to create recombinant viruses with desired properties. Custom adenoviruses can be created that target specific cell types or tissue, evade the host immune system or express exogenous protein such as pro-drug converting enzymes. In addition, multiple-protein complexes and entire pathways can be assembled, delivered, and co-expressed via adenoviral infection.

This platform allows for the optimization of viruses for use in oncolytic viral therapies, enabling the development of viruses that can avoid liver toxicity, evade neutralizing antibodies, efficiently target and cross the tumor vasculature, infect cells via different cell-surface receptors and reactivate beneficial host antitumor immune responses. Investigators used this platform to optimize for novel oncolytic viruses, which can replicate specifically in cancer cells and not normal cells.

Viruses have been generated, which specifically target cancer cells that were either defective for p53 or Rb/p16. The respective viruses were able to infect, replicate and kill cancer cells without deleterious effects on normal cells. This technology overcomes many of the challenges associated with the generation of novel adenoviral genomes and their subsequent application, and is a promising new tool for the development of novel research reagents, diagnostics and therapeutics.

 

APPLICATIONS:

  • Functional virology
  • Vaccine development
  • Development of targeted therapies
  • Development of oncolytic and gene delivery therapies
  • Phenotypic interrogation of the defective pathways in circulating tumor cells, tissue samples and other material
  • In vivo and in vitro expression in difficult-to-transduce cell types and tissues

ADVANTAGES

  • Ability to manipulate the 36kb viral genome rapidly and systematically
  • Library-based
  • Can target nearly any cell type or tissue type
  • Ability to combine parts of viral genomes from various serotypes
  • Can generate human/mouse chimeras for use in genetically engineered mouse models of cancer (GEMMs)
  • Can generate novel adenoviruses that can evade neutralizing antibodies produced to Ad2/5 adenoviruses
  • Efficient expression and delivery of multi-protein complexes and entire pathways
  • Allows for generation of either replication-defective or replication-competent virus

BACKGROUND: There are well over 50 human adenoviruses and hundreds that infect other species from fish to humans. Each of these viruses has unique capabilities for tissue targeting and replication, immune evasion, and host cell manipulation. As DNA viruses, they do not integrate into host DNA, can be produced to high titers using established GMP protocols, and have demonstrated safety in human gene therapy and oncolytic virus therapy. Although adenovirus is one of the most commonly used gene transfer vectors in basic and pre-clinical research, their potential applications have been limited to almost exclusive use of the adenovirus 5 strain.  This new platform technology unlocks the natural power of thousand of years of evolution by creating a modular, rapid and systematic assembly method, thus allowing for the creation of thousands of novel recombinant adenoviral vectors for a myriad of uses.  
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INVENTORS: Clodagh O'Shea and Colin Powers 
PATENT STATUS: US Patent Appl No. 2013/0231267, Australia, Brazil, Canada, China, Europe, India, Japan, Korea
PUBLICATION: In preparation
CONTACT: Michelle A. Booden, Ph.D., 858.453.4100 x1612, mbooden@salk.edu
REFERENCE #: S10004
Patent Information:
For Information, Contact:
Michelle Booden
Director, Licensing and Intellectual Property
Salk Institute
mbooden@salk.edu
Inventors:
Keywords:
Adenovirus
Cancer Diagnostics
Cancer Therapeutics
Cancer Vaccines
DNA Virus
Gene Delivery
Gene Expression
Gene Therapy
Immunotherapies
Oncology
Oncolytic Therapy
O'Shea
Targeted Therapies
Vaccine
Viral Vectors
Virus
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