Viral Vectors in Gene Therapy

Lundström, Kenneth

doi:10.3390/diseases6020042

Cited by 348 publications

(224 citation statements)

References 122 publications

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“…Safety concerns regarding initial GT studies using insertional vectors in the 1990s included the death of a patient following adenoviral therapy for ornithine transcarbamylase and multiple leukaemia cases following a retroviral therapy for severe combined immunodeficiency and Wiskott-Aldrich syndrome. [9][10][11][12][13] More recently, rAAV vectors have been used most commonly as they effectively transduce target cells but have a lower risk of immunogenicity compared with adenoviral vectors and have a low risk of genotoxicity versus insertional vectors. 14 AAV is internalised into target cells by binding to specific cell-surface receptors and is trafficked to the nucleus.…”

Section: Joint Damage Despite Factor Prophylaxismentioning

confidence: 99%

How to discuss gene therapy for haemophilia? A patient and physician perspective

et al. 2019

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Gene therapy has the potential to revolutionise treatment for patients with haemophilia and is close to entering clinical practice. While factor concentrates have improved outcomes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life. Recently published studies in adeno‐associated viral (AAV) vector‐mediated gene therapy have demonstrated improvement in endogenous factor levels over sustained periods, significant reduction in annualised bleed rates, lower exogenous factor usage and thus far a positive safety profile. In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long‐term safety profiles and duration of treatment effect. The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre‐existing neutralising AAV antibodies. Gene therapy offers a life‐changing opportunity for patients to reduce their bleeding risk while also reducing or abrogating the need for exogenous factor administration. Given the expanding evidence base, both physicians and patients will need sources of clear and reliable information to be able to discuss and judge the risks and benefits of treatment.

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Section: Joint Damage Despite Factor Prophylaxismentioning

confidence: 99%

How to discuss gene therapy for haemophilia? A patient and physician perspective

et al. 2019

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“…While the tropism of lenti and adenoviral vectors would be broadly similar, the protein capsid of adenoviral vectors renders them considerably more robust than lentiviral vectors, and thus more likely to persist in circulation long enough to infect unintended cell populations (33).…”

Section: Discussionmentioning

confidence: 99%

“…As is the case for off-target tumour incidence, we suspect that choice and/or dose of vector may largely explain the difference in tumour histology. Specifically, adenoviral vectors are profoundly more immunogenic than lentiviral vectors and this immunogenicity may well influence the trajectory of the nascent tumour phenotype (33). Notably, whereas loss of BAP1 is enriched in human epithelioid MPM (13), the recently reported adeno-Cre induced mouse models incorporating a floxed Bap1 allele both yielded sarcomatoid phenotypes (20,21).…”

Section: Discussionmentioning

confidence: 99%

Asbestos accelerates disease onset in a genetic model of Malignant Pleural Mesothelioma

Farahmand

Gyurászová

Rooney

et al. 2020

Preprint

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Hypothesis:Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations.Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration.

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“…Second, they enable preclinical research in rodents and primates to demonstrate causality between network dysfunction and disease hallmarks (Kastanenka et al, ). Third, advances in viral vector technology for gene transfer significantly reduce vector‐associated cytotoxicity and immune responses (Lundstrom, ), rendering chemogenetics and optogenetics amenable for clinical use in human patients.…”

Section: A Roadmap To Advance the Integration Of Astrocytes Into Systmentioning

confidence: 99%

A roadmap to integrate astrocytes into Systems Neuroscience

Kastanenka

Moreno-Bote

Pittà

et al. 2019

Glia

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Systems neuroscience is still mainly a neuronal field, despite the plethora of evidence supporting the fact that astrocytes modulate local neural circuits, networks, and complex behaviors. In this article, we sought to identify which types of studies are necessary to establish whether astrocytes, beyond their well‐documented homeostatic and metabolic functions, perform computations implementing mathematical algorithms that sub‐serve coding and higher‐brain functions. First, we reviewed Systems‐like studies that include astrocytes in order to identify computational operations that these cells may perform, using Ca2+ transients as their encoding language. The analysis suggests that astrocytes may carry out canonical computations in a time scale of subseconds to seconds in sensory processing, neuromodulation, brain state, memory formation, fear, and complex homeostatic reflexes. Next, we propose a list of actions to gain insight into the outstanding question of which variables are encoded by such computations. The application of statistical analyses based on machine learning, such as dimensionality reduction and decoding in the context of complex behaviors, combined with connectomics of astrocyte–neuronal circuits, is, in our view, fundamental undertakings. We also discuss technical and analytical approaches to study neuronal and astrocytic populations simultaneously, and the inclusion of astrocytes in advanced modeling of neural circuits, as well as in theories currently under exploration such as predictive coding and energy‐efficient coding. Clarifying the relationship between astrocytic Ca2+ and brain coding may represent a leap forward toward novel approaches in the study of astrocytes in health and disease.

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Viral Vectors in Gene Therapy

Cited by 348 publications

References 122 publications

How to discuss gene therapy for haemophilia? A patient and physician perspective

How to discuss gene therapy for haemophilia? A patient and physician perspective

Asbestos accelerates disease onset in a genetic model of Malignant Pleural Mesothelioma

A roadmap to integrate astrocytes into Systems Neuroscience

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