Adenovirus sensing by the immune system

Atasheva, Svetlana; Shayakhmetov, Dmitry M.

doi:10.1016/j.coviro.2016.08.017

Cited by 49 publications

(30 citation statements)

References 33 publications

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“…However, AAV-based strategies are cautioned by increasing reports of unintended and potentially hazardous off-target integration events [ 53 – 58 ]. Despite a well-characterized immune response to adenoviral vectors [ 59 ] and a likely in vivo immune response against Cas9 per se [ 60 ], our work showed that knock-in gene editing via adenoviral vector is efficient enough to persist over time and did not have overt detrimental effects on the animals' health. Our results, taken with an overall lack of mortality in the study, allow the conclusion that adenovirus vector-mediated knock-in was well tolerated in the animals, contrary to a previous report of adenovirus as unsuitable for therapeutic gene editing [ 12 ].…”

Section: Discussionmentioning

confidence: 80%

Targeted in vivo knock-in of human alpha-1-antitrypsin cDNA using adenoviral delivery of CRISPR/Cas9

et al. 2018

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Serum deficiency diseases such as alpha-1-antitrypsin deficiency are characterized by reduced function of serum proteins, caused by deleterious genetic mutations. These diseases are promising targets for genetic interventions. Gene therapies using viral vectors have been used to introduce correct copies of the disease-causing gene in pre-clinical and clinical studies. However, these studies highlighted that disease-alleviating gene expression is lost over time. Integration into a specific chromosomal site could provide lasting therapeutic expression to overcome this major limitation. Additionally, targeted integration could avoid detrimental mutagenesis associated with integrative vectors, such as tumorigenesis or functional gene perturbation. To test if adenoviral vectors can facilitate long-term gene expression through targeted integration, we somatically incorporated the human alpha-1-antitrypsin gene into the ROSA26 ‘safe harbor’ locus in murine livers, using CRISPR/Cas9. We found adenoviral-mediated delivery of CRISPR/Cas9 achieved gene editing outcomes persisting over two hundred days. Furthermore, gene knock-in maintained greater levels of the serum protein than provided by episomal expression. Importantly, our ‘knock-in’ approach is generalizable to other serum proteins and supports in vivo cDNA replacement therapy to achieve stable gene expression.

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Section: Discussionmentioning

confidence: 80%

Targeted in vivo knock-in of human alpha-1-antitrypsin cDNA using adenoviral delivery of CRISPR/Cas9

et al. 2018

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“…Viral vectors and non-viral nanoparticles are taken up by monocytes and macrophages in various tissues, specifically within the liver and spleen, and the incoming particle and DNA or RNA is sensed by innate immune mechanism. This results in release and activation of pro-inflammatory cytokines 68 . It is thought that AAV vectors provoke weaker innate immune responses than other viral vectors such as Ad or LV 69 , however, at this point no direct comparisons of these vector systems with regards to innate toxicity have been made following IV injection.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Hematopoietic Stem Cell Transduction

Richter

Stone

Miao

et al. 2017

Hematology/Oncology Clinics of North America

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Synopsis Current hematopoietic stem cell (HSC) gene therapy approaches rely on the collection of patient HSCs, followed by their culture and expansion in vitro, their modification using γ-retrovirus or lentiviral vectors, and their re-infusion into myelo-conditioned patients. While this approach has been successfully used in numerous clinical trials, its reliance on the extended ex vivo culture of patient HSCs comes with a set of disadvantages. Culturing HSCs in the presence of a cytokine cocktail to facilitate their expansion and transduction is thought to negatively impact the long-term viability of HSCs, and their homing and repopulation capacity. Importantly, the requirement for myeloablative regimens in patients represents a critical risk factor and results in considerable morbidity. In addition to these biological problems, the process of ex vivo HSC manipulation is also challenging from a logistics and regulatory standpoint, as manipulations must be performed in specialized, accredited centers. These complexities lead to a high price of such gene therapeutic regimens, and subsequently severely limited patient access to these treatments. In vivo HSC gene therapy approaches aim to simplify the gene therapy process by eliminating the need for ex vivo handling of patient HSCs. The in vivo approach can be subdivided into three methods. One method is based on the direct modification of HSCs in the bone marrow following intraosseous injection. Another involves intravenous injection of gene delivery vectors that home to HSCs in bone marrow. We have developed an alternative approach in which HSCs from the bone marrow are mobilized into peripheral blood, become gene modified upon intravenous vector administration, and then re-engraft in the bone marrow. We will provide examples of these three approaches and then discuss the advantages and disadvantages of in vivo HSC gene therapy.

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“…The interactions impacting Ad biodistribution upon intravascular delivery have been widely described. Reasons for the low efficacy of Ad5-derived vectors include clearance after opsonization by natural antibodies and complement, as well as sequestration in the liver and spleen mediated by binding with human coagulation factor 10 (FX) and other coagulation factors to HSPG abundant on hepatocytes or scavenger receptors on Kupffer cells [136][137][138]. Since a small portion of the Ad particles injected ip are able to enter the circulation, Ad vectors administered through this route are susceptible to clearance after interacting with blood components and residential macrophages in tissue and in the peritoneal cavity [83,139].…”

Section: Overcoming Physical Barriers To Dissemination Of Oncolytic Amentioning

confidence: 99%

Understanding and addressing barriers to successful adenovirus-based virotherapy for ovarian cancer

2020

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Ovarian cancer is the leading cause of death among women with gynecological cancer, with an overall 5-year survival rate below 50% due to a lack of specific symptoms, late stage at time of diagnosis and a high rate of recurrence after standard therapy. A better understanding of heterogeneity, genetic mutations, biological behavior and immunosuppression in the tumor microenvironment have allowed the development of more effective therapies based on anti-angiogenic treatments, PARP and immune checkpoint inhibitors, adoptive cell therapies and oncolytic vectors. Oncolytic adenoviruses are commonly used platforms in cancer gene therapy that selectively replicate in tumor cells and at the same time are able to stimulate the immune system. In addition, they can be genetically modified to enhance their potency and overcome physical and immunological barriers. In this review we highlight the challenges of adenovirus-based oncolytic therapies targeting ovarian cancer and outline recent advances to improve their potential in combination with immunotherapies.

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Adenovirus sensing by the immune system

Cited by 49 publications

References 33 publications

Targeted in vivo knock-in of human alpha-1-antitrypsin cDNA using adenoviral delivery of CRISPR/Cas9

Targeted in vivo knock-in of human alpha-1-antitrypsin cDNA using adenoviral delivery of CRISPR/Cas9

In Vivo Hematopoietic Stem Cell Transduction

Understanding and addressing barriers to successful adenovirus-based virotherapy for ovarian cancer

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