combined-genetic-chemical-capsid-modifications-adenovirus-based-gene

Combined Genetic and Chemical Capsid Modifications of Adenovirus-Based Gene Transfer Vectors for Shielding and Targeting

Adenovirus vectors are potent tools for genetic vaccination and oncolytic virotherapy. However, they are prone to multiple undesired vector-host ...

University Witten/Herdecke

Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response.

TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall.

Currently, virus-based vectors, namely derivatives of the adenovirus, are frequently used in a wide variety of ex vivo or local gene therapeutic applications. However, the efficacy of virus-based vectors in systemic applications is presently still extremely limited. Complex interactions of the various vector types with the patient's organism hinder successful vector deployment. Exemplary, here we summarize barriers to systemic application of Adenovirus-based vectors leading either to acute toxic effects or rapid vector neutralization and discuss strategies to overcome these barriers aiming to develop more efficient vector types.

Barriers to systemic application of virus-based vectors in gene therapy: lessons from adenovirus type 5.

Virotherapy is a unique modality for the treatment of cancer with oncolytic viruses (OVs) that selectively infect and lyse tumor cells, spread within tumors, and activate anti-tumor immunity. Various viruses are being developed as OVs preclinically and clinically, several of them engineered to encode therapeutic proteins for tumor-targeted gene therapy. Scientists and clinicians in German academia have made significant contributions to OV research and development, which are highlighted in this review paper. Innovative strategies for "shielding," entry or postentry targeting, and "arming" of OVs have been established, focusing on adenovirus, measles virus, parvovirus, and vaccinia virus platforms. Thereby, new-generation virotherapeutics have been derived. Moreover, immunotherapeutic properties of OVs and combination therapies with pharmacotherapy, radiotherapy, and especially immunotherapy have been investigated and optimized. German investigators are increasingly assessing their OV innovations in investigator-initiated and sponsored clinical trials. As a prototype, parvovirus has been tested as an OV from preclinical proof-of-concept up to first-in-human clinical studies. The approval of the first OV in the Western world, T-VEC (Imlygic), has further spurred the involvement of investigators in Germany in international multicenter studies. With the encouraging developments in funding, commercialization, and regulatory procedures, more German engineering will be translated into OV clinical trials in the near future.

Virotherapy Research in Germany: From Engineering to Translation.

From Virus to vector to medicine: Foreword by guest editors.

Vectors based on human adenovirus are highly efficient tools for transient genetic modifications of cells or tissues in vitro and in vivo. They can be utilized for gene addition strategies, knockdown strategies and as transfer vectors for designer nucleases and CRISPR/Cas. They are characterized by high genomic stability and can be produced to high titers. This chapter describes the method how to produce, purify and titrate adenovirus vectors based on human adenovirus type 5.

Article	Year
TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 28716576	2017
Barriers to systemic application of virus-based vectors in gene therapy: lessons from adenovirus type 5. Virus genes\| PubMed ID: 28755290	2017
Virotherapy Research in Germany: From Engineering to Translation. Human gene therapy\| PubMed ID: 28870120	2017
From Virus to vector to medicine: Foreword by guest editors. Virus genes\| PubMed ID: 28921483	2017
Production, Purification, and Titration of First-Generation Adenovirus Vectors. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 28986806	2017

Florian Kreppel

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