Liver-directed lentiviral gene therapy in a dog model of hemophilia B

Cantore, Alessio; Ranzani, Marco; Bartholomae, Cynthia C.; Volpin, Monica; Valle, Patrizia Della; Sanvito, Francesca; Sergi, Lucia Sergi; Gallina, Pierangela; Benedicenti, Fabrizio; Bellinger, Dwight A.; Raymer, Robin A.; Merricks, Elizabeth P.; Bellintani, Francesca; Martin, Samia; Doglioni, Claudio; D’Angelo, Armando; VandenDriessche, Thierry; Chuah, Marinee; Schmidt, Manfred; Nichols, Timothy C.; Montini, Eugenio; Naldini, Luigi

doi:10.1126/scitranslmed.aaa1405

Cited by 121 publications

(155 citation statements)

References 51 publications

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“…Several wild-type AAV serotypes display inherent hepatic targeting (see also Delivery to target cells below) and their non-pathogenic track record makes them ideally suited for in-vivo gene therapy. However, other viruses have been successfully used in non-clinical models, including rLV [56], HD-Ad [57] and exosome-enveloped rAAV [58]. …”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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“…37 VSV-G pseudotyped third generation lentiviral vectors expressing the amiRs were produced by transient four plasmid cotransfection into HEK293T cells and concentrated by ultracentrifugation. 38 Tumor cells were transduced with increasing multiplicity of infection (MOI) of the Hmgb1 or the LacZ a-miR LV. Infected cells (MOI 25) were sorted for mOrange.…”

Section: Adenocarcinoma Cell Lines and Genetic Manipulationmentioning

confidence: 99%

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

et al. 2016

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The factors that determine whether disseminated transformed cells in vivo yield neoplastic lesions have only been partially identified. We established an ad hoc model of peritoneal carcinomatosis by injecting colon carcinoma cells in mice. Tumor cells recruit inflammatory leukocytes, mostly macrophages, and generate neoplastic peritoneal lesions. Phagocyte depletion via clodronate treatment reduces neoplastic growth. Colon carcinoma cells release a prototypic damage-associated molecular pattern (DAMP)/alarmin, High Mobility Group Box1 (HMGB1), which attracts leukocytes. Exogenous HMGB1 accelerates leukocyte recruitment, macrophage infiltration, tumor growth and vascularization. Lentiviral-based HMGB1 knockdown or pharmacological interference with its extracellular impair macrophage recruitment and tumor growth. Our findings provide a preclinical proof of principle that strategies based on preventing HMGB1-driven recruitment of leukocytes could be used for treating peritoneal carcinomatosis.

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“…51 Lentiviral vectors could be an alternative for these patients; however, data from translational studies in large animal models using in vivo or ex vivo strategies are challenging. 74,75 Last, the excitement over the potential of these novel therapies to improve the lives of people of with hemophilia in the developed world should not conceal the economic reality that, because of costs, .75% of the hemophilia worldwide population (;350 000) is not regularly, if at all, treated. Closing this treatment gap between patients in the developed and the developing world remains an unmet ethical imperative.…”

Section: Resultsmentioning

confidence: 99%

Novel approaches to hemophilia therapy: successes and challenges

Arruda

Doshi

Samelson-Jones

2017

Blood

106

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New therapies for hemophilia A and hemophilia B will likely continue to change clinical practice. Ranging from extended half-life to nonfactor products and gene therapy, these innovative approaches have the potential to enhance the standard of care by decreasing infusion frequency to increase compliance, promoting prophylaxis, offering alternatives to inhibitor patients, and easing route of administration. Each category has intrinsic challenges that may limit the broader application of these promising therapies. To date, none specifically address the challenge of dispersing treatment to the developing world.

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Liver-directed lentiviral gene therapy in a dog model of hemophilia B

Cited by 121 publications

References 51 publications

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

Novel approaches to hemophilia therapy: successes and challenges

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