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Cited by 218Virus-based gene therapy researchRNA Interference and Gene DeliveryViral Infectious Diseases and Gene Expression in Insects

Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges

Open access
Ghosh, Sumit, Brown, Alex M., Jenkins, Chris, Campbell, Katie·2020·Applied Biosafety
DOI 10.1177/1535676019899502PMC PMC9134621
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Abstract

Introduction: National Institutes of Health (NIH) defines gene therapy as an experimental technique that uses genes to treat or prevent disease. Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be effective and safe. Methods: Applications of viral vectors and nonviral gene delivery systems have found an encouraging new beginning in gene therapy in recent years. Although several viral vectors and nonviral gene delivery systems have been developed in the past 3 decades, no one delivery system can be applied in gene therapy to all cell types in vitro and in vivo. Furthermore, the use of viral vector systems (both in vitro and in vivo) present unique occupational health and safety challenges. In this review article, we discuss the biosafety challenges and the current framework of risk assessment for working with the viral vector systems. Discussion: The recent advances in the field of gene therapy is exciting, but it is important for scientists, institutional biosafety committees, and biosafety officers to safeguard public trust in the use of this technology in clinical trials and make conscious efforts to engage the public through ongoing forums and discussions.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes five main viral vector classes used in gene therapy and the biosafety/risk-assessment challenges they pose. It argues that despite clinical progress, the absence of consensus guidelines and limited shedding/risk data complicate institutional biosafety committee oversight.

Key findings

  • As of 2019, almost 2600 gene therapy clinical trial studies had been completed, were ongoing, or had been approved worldwide; 232 gene and cell therapy trials had been approved worldwide; 4 FDA-approved gene therapy products were available in the United States; and almost 70% of gene therapy trials were based on viral vectors.
  • The review covers 5 main viral vector classes: retroviruses (RV), adenoviruses (AV), adeno-associated viruses (AAV), lentiviruses (LV), and herpes simplex viruses (HSV). It categorizes them by whether their genomes integrate into host chromatin (oncoretroviruses and LV) or persist predominantly as extrachromosomal episomes (AAV, AV, and herpes viruses).
  • Vector-specific biosafety and efficacy points include: AAV is generally handled at BSL-1, has a packaging capacity generally considered <5 kb, and approximately 80% of humans are seropositive to AAV strains; AV is handled at BSL-2 and is immunogenic, with 1 documented death after direct injection of an adenoviral vector into the hepatic artery; RV and LV carry insertional mutagenesis/oncogene activation risks; HSV is handled at BSL-2 and remains a known human pathogen, with approximately 53% HSV-1 and 16% HSV-2 seroprevalence in the United States.
  • The paper reports no consensus framework for comprehensive risk assessment of viral vector systems. It notes limited peer-reviewed shedding data, that some vectors can be excreted in blood, urine, saliva, and stool for up to a week after injection, and that most health care facilities recommend universal/standard precautions with patient material between 14 and 30 days after administration; ZOLGENSMA product information recommends 30-day universal or standard precautions.

Methods

  • Narrative/comprehensive literature review of viral vector systems for gene therapy and associated biosafety challenges, not primary research.
  • Draws on published literature and guidelines from NIH, WHO, CDC, BMBL, and FDA-approved gene therapy product information; discusses vector biology, clinical applications, risk group/biosafety level recommendations, and institutional review processes.
  • No systematic search strategy, databases, search dates, or inclusion/exclusion criteria are stated.

Limitations

  • The paper states that there is no single document summarizing guidelines for working with viral vectors, minimal information for conducting comprehensive risk assessment in health care research settings, no consensus framework for risk assessment, limited peer-reviewed publications outlining shedding data, and no summary of actual shedding data for different viral vector systems; it also notes no standards govern thresholds for replication-competent virus contamination.
  • The text makes evident that this is a narrative review without a systematic search or primary data, and it states that long-term safety of LV clinical interventions is still being evaluated.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1177/1535676019899502

Cites

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingcitation

    AAV8 demonstrated higher levels, up to 100-fold higher, of factor IX expression in liver cells than for any other AAV serotype tested.

    “In particular, AAV8 demonstrated higher levels (up to 100-fold higher) of factor IX expression in liver cells than for any other AAV serotype tested.”
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    Some first-generation adenoviral vectors, which retain a considerable proportion of the genome, have initiated dose-dependent apoptosis of various target cells in vitro and in multiple mouse models in vivo, indicating a potential for direct cytotoxicity.

    “Some firstgeneration adenoviral vectors, which retain a considerable proportion of the genome, have initiated dose-dependent apoptosis of various target cells in vitro and in multiple mouse models in vivo, indicating a potential for direct cytotoxicity.”
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    Several gene clinical trials have revealed that AAV vectors do not stimulate a heightened immune response.

    “Moreover, several gene clinical trials have revealed that AAV vectors do not stimulate a heightened immune response.”
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    To date, 5 main classes of viral vectors have been tested for clinical applications: retroviruses, adenoviruses, adeno-associated viruses, lentiviruses, and herpes simplex viruses.

    “To date, 5 main classes of viral vectors have been tested for clinical applications.25,27 These include retroviruses (RV), adenoviruses (AV), adenoassociated viruses (AAV), lentiviruses (LV), and herpes simplex viruses (HSV).”
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    The majority of gene therapy trials, almost 70%, are based on viral vectors.

    “The majority of these gene therapy trials, almost 70%, are based on viral vectors.”
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    Findingcitation

    Several episodes of inflammatory responses to AV vectors in clinical trials have been documented, including 1 death after direct injection of an adenoviral vector into the hepatic artery.

    “Several episodes of inflammatory responses to AV vectors in clinical trials have been documented, including 1 death after direct injection of an adenoviral vector into the hepatic artery.”
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    In some animal models, the integration of recombinant AAV increased the incidence of tumor formation, but this association has not been observed in humans.

    “In some animal models, the integration of recombinant AAV increased the incidence of tumor formation, but this association has not been observed in humans.”
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    The choice of viral vectors for clinical use depends on the efficiency of transgene expression, ease of production, safety, toxicity, and stability.

    “The choice of viral vectors for clinical use depends on the efficiency of transgene expression, ease of production, safety, toxicity, and stability.”
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    The resulting AAV vector can transduce both dividing and nondividing cells, with stable transgene expression in the absence of the helper virus in postmitotic tissue.

    “The significant advantage is that the resulting vector can transduce both dividing and nondividing cells, with stable transgene expression in the absence of the helper virus in postmitotic tissue.”
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    The use of viral vector systems, both in vitro and in vivo, presents unique occupational health and safety challenges.

    “Furthermore, the use of viral vector systems (both in vitro and in vivo) present unique occupational health and safety challenges.”
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    The CDC, WHO, and NIH have published recommendations for work at different biosafety levels (BSL-1 to BSL-4) for wild-type virus and viral vector handling in a laboratory research setting.

    “The Centers for Disease Control and Prevention (CDC), WHO, and NIH have published recommendations for work at different biosafety levels (BSL-1 to BSL-4) for wild-type virus and viral vector handling in a laboratory research setting.”
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    Premisecitation

    Historically, IBCs have been responsible for reviewing any risks associated with viral shedding and insertional mutagenesis during the protocol review process.

    “Historically, IBCs have been responsible for reviewing any risks associated with viral shedding and insertional mutagenesis during the protocol review process.”
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    The risk group informs about the level of containment needed to minimize risk during the handling of these infectious agents as designated by its biosafety level.

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    Some viral vectors, such as adenovirus vectors and herpesviral vectors, are toxic and can be immunogenic.

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    The integration of AAV into the host genome, if it occurs at all, is random and can lead to accidental activation or inhibition of endogenous gene expression.

    “The preexisting immunity to human AAV vectors is comparable to the AV, and the integration into the host genome (if it occurs at all) is random, which can lead to accidental activation or inhibition of endogenous gene expression.”
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    When viral vector systems are used in gene therapy experiments in a clinical setting, these recommendations are adapted to do a comprehensive risk assessment and for developing a mitigation plan.

    “When viral vector systems are used in gene therapy experiments in a clinical setting, these recommendations are adapted to do a comprehensive risk assessment and for developing a mitigation plan.”
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    The NIH Recombinant DNA Guidelines and the WHO Laboratory Biosafety Manual categorize infectious agents into risk groups for laboratory research (Risk Groups 1-4).

    “The National Institutes of Health (NIH) Recombinant DNA Guidelines and the World Health Organization (WHO) Laboratory Biosafety Manual categorize infectious agents into risk groups for laboratory research (Risk Groups 1-4).”
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    Retroviral vectors have been extensively used to deliver therapeutic genes in the context of gene therapy, clinical applications for monogenic disorders, cancer, and infectious diseases, providing a stable and efficient expression of the transgene to patients.

    “Retroviral vectors have been extensively used to deliver therapeutic genes in the context of gene therapy, clinical applications for monogenic disorders, cancer, and infectious diseases, providing a stable and efficient expression of the transgene to patients.”
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    Replication-competent retroviruses also cause malignant disease and a range of other pathogenic states in a wide variety of species.

    “Replication-competent retroviruses also cause malignant disease and a range of other pathogenic states in a wide variety of species.”
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    Adenoviral vector particles themselves elicit cellular inflammatory responses as opposed to relatively inert AAV virions.

    “Another concern with adenoviral vectors, in general, is that the particles themselves elicit cellular inflammatory responses as opposed to relatively inert AAV virions.”
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    Interpretationreasoning

    Human cells are easily infected with AV vectors and consequently yield high levels of transgene expression.

    “Thus, human cells are easily infected with AV vectors and consequently yield high levels of the transgene expression.”
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    Premisecitation

    Gutless adenoviral vectors have a carrying capacity of more than 30 kb but are currently challenging to manufacture.

    “Although these adenoviral genes have a carrying capacity of more than 30 kb, they are currently challenging to manufacture.”
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    Currently, researchers have determined threshold levels for replication-competent virus contamination arbitrarily because no standards govern thresholds to date.

    “Currently, researchers have determined these threshold levels arbitrarily because no standards govern thresholds to date.”
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    Premisecitation

    AAV is generally handled at BSL-1.

    “AAV is generally handled at BSL-1.”
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    The AV is the most effective means of delivering genes in vivo as most human cells express the primary AV receptor and the secondary integrin receptors.

    “First, the AV is the most effective means of delivering genes in vivo as most human cells express the primary AV receptor and the secondary integrin receptors.”
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    Premisecitation

    Standard recombinant adenoviral vectors have the E1 unit deleted, but the removal of E3 can create vectors capable of packaging up to 7.5 kb of foreign DNA.

    “Standard recombinant adenoviral vectors have the E1 unit deleted, but the removal of E3 can create vectors capable of packaging up to 7.5 kb of foreign DNA.”
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    While AAV can infect humans and other primate species, AAV is not known to cause disease.

    “While AAV can infect humans and other primate species, AAV is not known to cause disease.”
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    Another risk-reduction strategy is regular quality control checks of viral vector stocks for possible low levels of contamination with the replication-competent virus.

    “Another risk-reduction strategy is regular quality control checks of viral vector stocks for possible low levels of contamination with the replication-competent virus.”
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    Work with AV vectors is done using BSL-2 practices.

    “Work with AV vectors is done using BSL-2 practices.”
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    Premisecitation

    In helper-dependent, or gutless, adenoviral vectors, all adenoviral genes are deleted, and a helper virus provides adenoviral genes for production.

    “Finally, in helper-dependent, or gutless, adenoviral vectors, all adenoviral genes are deleted, and a helper virus provides adenoviral genes for production.”
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    Premisecitation

    Although AV cause mild respiratory disease or conjunctivitis in healthy adults, they are notoriously immunogenic.

    “Although AV cause mild respiratory disease or conjunctivitis in healthy adults, they are notoriously immunogenic.”
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    Premisecitation

    AAV has the potential for replication competence in the presence of a helper plasmid or virus, and stock solutions should be tested for the presence of other agents.

    “Although ineffective in replication as an isolated agent, AAV has the potential for replication competence in the presence of a helper plasmid or virus, and stock solutions should be tested for the presence of other agents.”
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    These vector systems are handled at BSL-2.

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    HSV is transmitted by direct contact and mucous membrane exposure to body excretions and respiratory droplets.

    “HSV is transmitted by direct contact and mucous membrane exposure to body excretions and respiratory droplets.”
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    Lentiviruses, a type of RV, consist of a single-stranded positive-sense RNA sequence that is transcribed into a DNA and integrated into the host genome, causing persistent infection.

    “Lentiviruses, a type of RV, consist of a single-stranded positive-sense RNA sequence that is transcribed into a DNA and integrated into the host genome, causing persistent infection.”
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    The use of LVVs in research is still associated with potential risks, and the long-term safety of these clinical interventions is still being evaluated.

    “The use of LVVs in research is still associated with potential risks, and the long-term safety of these clinical interventions is still being evaluated.”
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    Premisecitation

    Amplicons are gene delivery systems packaged through transfection into producer cells of plasmids containing the HSV origin of DNA replication, HSV cleavage-packaging sequences, and transgene(s) of interest.

    “First, amplicons are gene delivery systems packaged through transfection into producer cells of plasmids containing the HSV origin of DNA replication, HSV cleavage-packaging sequences, and transgene(s) of interest.”
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    Although molecular alterations to the viral genome have dramatically reduced virus-associated risks, HSV remains a known human pathogen with inflammatory and immunomodulatory effects.

    “Although molecular alterations to the viral genome have dramatically reduced virus-associated risks, HSV remains a known human pathogen with inflammatory and immunomodulatory effects.”
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    Premisecitation

    Replication-competent vectors serve as oncolytic therapies and vaccines, where the set of deleted genes must lead to the appropriate balance of replicative attenuation for safety and lytic activity for tumor toxicity or vaccine immunogenicity, respectively.

    “Replicationcompetent vectors serve as oncolytic therapies and vaccines, where the set of deleted genes must lead to the appropriate balance of replicative attenuation for safety and lytic activity for tumor toxicity or vaccine immunogenicity, respectively.”
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    Most lentiviral vectors (LVVs) are derived from HIV-1 and retain the capability to integrate into the genome of infected cells.

    “Most lentiviral vectors (LVVs) are derived from HIV-1 and retain the capability to integrate into the genome of infected cells.”
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    HSV-1 is a neurotropic virus that displays numerous necessary adaptations to the nervous system.

    “HSV-1 is a neurotropic virus that displays numerous necessary adaptations to the nervous system.”
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    Although LVVs are less associated with insertional mutagenesis than other RV, these vectors still provide evidence of off-target effects.

    “Although LVVs are less associated with insertional mutagenesis than other RV, these vectors still provide evidence of off-target effects.”
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    The plasmids form head-to-tail linked concatemers that are packaged into the viral particles, which can, in general, accommodate large fragments of foreign DNA.

    “The plasmids form head-to-tail linked concatemers that are packaged into the viral particles, which can, in general, accommodate large fragments of foreign DNA.”
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    The HSV genome encodes approximately 90 genes, almost half of which are nonessential and can be eliminated in recombinant vectors.

    “The HSV genome encodes approximately 90 genes, almost half of which are nonessential and can be eliminated in recombinant vectors.”
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    Incorporation of a virus envelope that can infect cells from multiple species increases both the risk of generating replication-competent retroviruses and the potential danger of any resulting virus, which could spread from one species to another.

    “Incorporation of a virus envelope that can infect cells from multiple species increases both the risk of generating replication-competent retroviruses and the potential danger of any resulting virus, which could spread from one species to another.”
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    The third-generation LVVs have the transactivator gene, tat, eliminated, which splits the vector into 3 plasmids to reduce further recombination potential, retaining only the 3 genes necessary for transgene expression (gag, pol, rev).

    “Additionally, the thirdgeneration LVVs have the transactivator gene, tat, eliminated, which splits the vector into 3 plasmids to reduce further recombination potential, retaining only the 3 genes necessary for transgene expression (gag, pol, rev).”
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    Most health care facilities recommend universal/standard precautions with patient material between 14 and 30 days after administration for both health care staff and direct family members, dependent on viral shedding analysis.

    “In general, most health care facilities recommend universal/standard precautions with patient material between 14 and 30 days after administration for both health care staff and direct family members, dependent on viral shedding analysis.128”
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    The NIH risk group for adenovirus is 2 and the recommended in vitro biosafety level is BSL-2.

    “2 BSL-2”
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    The revised NIH Guidelines (April 2019) eliminate the RAC review, protocol registration, and reporting requirements associated with gene therapy research.

    “The revised NIH Guidelines (April 2019) eliminate the RAC review, protocol registration, and reporting requirements associated with gene therapy research.”
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    In May 2019, the FDA approved Onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy in children.

    “Most recently in May 2019, the FDA approved Onasemnogene abeparvovec, sold under the trade name Zolgensma, a gene therapy medication to treat spinal muscular atrophy in children.131”
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    In October 2017, Yescarta became the first CAR T cell therapy approved by the FDA for use in adult patients.

    “Additionally, in October 2017, Yescarta (Kite Pharma Inc/Gilead) became the first CAR T cell therapy approved by the FDA for use in adult patients.23”
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    Premisereasoning

    Safe use of viral vector systems in human gene therapy research is a major concern for most IBCs in a research/clinical setting because there is no single document that summarizes the guidelines of working with them.

    “Safe use of viral vector systems in human gene therapy research is a major concern for most IBCs in a research/clinical setting because there is no single document that summarizes the guidelines of working with them.”
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    Premisecitation

    The IRB review is necessary to protect the rights and welfare of research subjects in clinical investigations.

    “The IRB review is necessary to protect the rights and welfare of research subjects in clinical investigations.”
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    Despite high seroprevalence of both HSV1 and HSV2 in the United States (approximately 53% and 16%, respectively), few robust data that support in vivo recombination or complementation are available.

    “Despite high seroprevalence of both HSV1 and HSV2 in the United States (approximately 53% and 16%, respectively), few robust data that support in vivo recombination or complementation are available.”
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    The revised NIH Guidelines highlight the critical role of IBCs in reviewing gene therapy research studies.

    “The revised NIH Guidelines highlight the critical role of IBCs in reviewing gene therapy research studies.”
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    Luxturna was the first virally delivered gene therapy and was approved in December 2017.

    “Luxturna (Spark Therapeutics), the first virally delivered gene therapy, was approved in December 2017.129”
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    The IRB review is necessary for research supported or conducted by any of the federal agencies subscribing to the Common Rule, for research on products regulated by FDA, and for research conducted by investigators at any institution giving Federalwide Assurance.

    “The IRB review is necessary for research supported or conducted by any of the federal agencies subscribing to the Common Rule, for research on products regulated by FDA, and for research conducted by investigators at any institution giving Federalwide Assurance (eg, universities assuring the federal government that all of their research will conform to federal rules on human subjects research).”
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    An IRB is also responsible for approving amendments to a study and review a progress report at least yearly.

    “An IRB is also responsible for approving amendments to a study and review a progress report at least yearly.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NIH risk group for AAV is 1 and the recommended in vitro biosafety level is BSL-1.

    “1 BSL-1 b”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1]

      Not checked in the free run.

    • cites [76] source

      Not checked in the free run.

    • cites [107]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    The CDC recommended biosafety level (in vivo) for adenovirus is ABSL-2.

    “ABSL-2 c”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53]

      Not checked in the free run.

    • cites [68]

      Not checked in the free run.

    • cites [107]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    It becomes very challenging for IBCs across organizations to develop a common framework for protocol review of gene therapy research by interpreting the recommendations outlined in BMBL and NIH Recombinant DNA guidelines.

    “As a result, it becomes very challenging for IBCs across organizations to develop a common framework for protocol review of gene therapy research by interpreting the recommendations outlined in BMBL and NIH Recombinant DNA guidelines.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is minimal information about conducting a comprehensive risk assessment when using viral vector systems or FDA-approved gene therapy products in a health care research setting.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Instructions are provided to family members and caregivers to practice good hand hygiene for a minimum of 2 weeks after the injection.

    “Additionally, instructions are provided to family members and caregivers to practice good hand hygiene for a minimum of 2 weeks after the injection.128”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NIH risk group for lentivirus is 3 (for HIV) and the recommended in vitro biosafety level is BSL-2.

    “3 (for HIV) BSL-2”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31]

      Not checked in the free run.

    • cites [82]

      Not checked in the free run.

    • cites [108]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In August 2017, the FDA approved Tisagenlecleucel (Kymriah) for B-cell acute lymphoblastic leukemia.

    “In August 2017, the FDA also approved the use of Tisagenlecleucel, marketed as Kymriah (Novartis), which is a treatment for B-cell acute lymphoblastic leukemia.130”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    The CDC recommended biosafety level (in vivo) for retrovirus, lentivirus, and herpesviral vector is ABSL-2.

    “ABSL-2 d”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [19]

      Not checked in the free run.

    • cites [26]

      Not checked in the free run.

    • cites [82]

      Not checked in the free run.

    • cites [31]

      Not checked in the free run.

    • cites [108]

      Not checked in the free run.

    • cites [9]

      Not checked in the free run.

    • cites [12]

      Not checked in the free run.

    • cites [91]

      Not checked in the free run.

    • cites [115]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The NIH Recombinant DNA guidelines and the fifth edition of Biosafety in Microbiological and Biomedical Laboratories (BMBL) offer the general framework of working with viral vectors, and they are often used as a reference for risk assessment for human gene transfer research.

    “The NIH Recombinant DNA guidelines and the fifth edition of Biosafety in Microbiological and Biomedical Laboratories (BMBL) offer the general framework of working with viral vectors, and they are often used as a reference for risk assessment for human gene transfer research.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Institutional policies govern how the organization institutional review board (IRB) interacts with IBCs during the human gene transfer research protocol review process.

    “Additionally, institutional policies govern how the organization institutional review board (IRB) interacts with IBCs during the human gene transfer research protocol review process.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The IRB requires a comprehensive review and approval for any research with human subjects supported by the U.S. Department of Health and Human Services (HHS) or regulated by FDA.

    “The IRB requires a comprehensive review and approval for any research with human subjects supported by the U.S. Department of Health and Human Services (HHS) or regulated by FDA.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118]

      Not checked in the free run.

    • cites [119]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An IRB has the authority to terminate or suspend any study for noncompliance.

    “Additionally, an IRB has the authority to terminate or suspend any study for noncompliance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A frequently asked question blog on the NIH website outlines the separation of the IBC with the IRB during the human gene therapy protocol review process.

    “In addition, a frequently asked question blog on the NIH website outlines the separation of the IBC with the IRB during the human gene therapy protocol review process.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An IRB has the authority to approve, require modifications to (as a condition of approval), or deny approval to gene therapy research and informed-consent documents.

    “An IRB has the authority to approve, require modifications to (as a condition of approval), or deny approval to gene therapy research and informedconsent documents.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119]

      Not checked in the free run.

66 of 66

  • The paper relies on this without support.

    There is no single document that summarizes the guidelines for working with viral vectors.

    “because there is no single document that summarizes the guidelines of working with them.”

  • The paper relies on this without support.

    There are limited resources available to institutional biosafety committees (IBCs) and health care providers for risk assessment and developing procedures to minimize risk and exposure in a research/clinical setting.

    “Additionally, there are limited resources available to institutional biosafety committees (IBCs) and health care providers when it comes to risk assessment and developing procedures to minimize risk and exposure in a research/clinical setting.”

  • The paper relies on this without support.

    There are no consensus guidelines for working with viral vector systems in a research/clinical setting because it is dictated by risk assessment.

    “given that there are no consensus guidelines for working with them in a research/ clinical setting because it is dictated by risk assessment.”

  • The paper relies on this without support.

    There is minimal information about conducting a comprehensive risk assessment when using viral vector systems or FDA-approved gene therapy products in a health care research setting.

    “However, there is minimal information about conducting a comprehensive risk assessment when using these vectors systems or FDA-approved gene therapy products in a health care research setting.”

  • The paper relies on this without support.

    No one delivery system can be applied in gene therapy to all cell types in vitro and in vivo.

    “Although several viral vectors and nonviral gene delivery systems have been developed in the past 3 decades, no one delivery system can be applied in gene therapy to all cell types in vitro and in vivo.”

  • The paper relies on this without support.

    There is currently no summary of actual shedding data available for different viral vector systems.

    “Despite the substantial number of clinical gene therapy trials that have been conducted worldwide, there is currently no summary of actual shedding data available for different viral vector systems.”

  • The paper relies on this without support.

    There are limited peer-reviewed publications that outline shedding data of different viral vector systems when administered to human research subjects.

    “However, there are limited peerreviewed publications that outline shedding data of different viral vector systems when administered to human research subjects.”

  • The paper relies on this without support.

    There is an absence of a consensus framework for the risk assessment process for gene therapy research using viral vector systems.

    “The design of new experimental viral vectors and emerging technologies highlight the critical role of biosafety professionals in managing gene therapy research protocols, identifying risk level, and developing acceptable policies predominantly in the absence of consensus framework for the risk assessment process.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • bioPROTACs would most likely be delivered as mRNA or DNA constructs via a viral vector gene delivery system or in a nanoparticle.

    “Indeed, bioPROTACs would most likely be delivered as mRNA or DNA constructs via a viral vector gene delivery system204–206 or in a nanoparticle207–209.”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [206]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Rep proteins described as both nonstructural and structural

    Minor

    The rep ORF is said to encode four nonstructural proteins, but the next sentence calls those proteins structural.

1 of 1

The citation lists haven’t been fetched yet

References 128 · Cited by 218

Research works printed but not linked: 20

  1. Boulaiz H, 2005, Cell Mol Biol (Noisy-le-grand), 51, 3
  2. Simón JE, 2018, Applied Biosafety, 52, 701
  3. Hansen JE, 2002, Ugeskr Laeger, 164, 4272
  4. 10.1177/1535676017694148 · DOI
  5. Hutchinson E, 1998, IDrugs, 1, 265
  6. Petrich J, J Pharm Pract
  7. Powell SK, 2015, Discov Med, 19, 49
  8. McClements ME, 2017, Yale J Biol Med, 90, 611
  9. Chang YX, 2019, Neural Plast, 3017678, 2019
  10. Goins WF, 2004, Methods Mol Biol, 246, 257
  11. Collins DE, 2017, Comp Med, 67, 215
  12. Rosewell A, 2011, J Genet Syndr Gene Ther, 001
  13. Liu J, 2008, Mol Vis, 14, 2087
  14. Günzburg WH, 1996, Cytokines Mol Ther, 2, 177
  15. Romano G, 2012, ISRN Oncol, 616310, 2012
  16. Ramezani A, 2002, Curr Protoc Mol Biol
  17. Sandoval Rodríguez AS, 2005, Rev Gastroenterol Mex, 70, 192
  18. Manservigi R, 2010, Open Virol J, 4, 123
  19. Raper S, 2016, Food Drug Law J, 71, 59
  20. 2019, Med Lett Drugs Ther, 61, 113

Authors
Ghosh, S., Brown, A. M., Jenkins, C., & Campbell, K.
Affiliations
  • Nationwide Children's Hospital (US)
  • Clinical Biosafety Services, A Division of Sabai Global, Wildwood, MO, USA
Corresponding author
Ghosh, Sumit
ORCID
Venue
Applied Biosafety
Publisher
SAGE Publications
Published
2020-03-01
Volume
25
Issue
1
Pages
7-18
ISSN
  • 1091-3505 (ISSN-L)
  • 1535-6760
  • 2470-1246
DOI
10.1177/1535676019899502
PMC
PMC9134621
OpenAlex
W3002722315
Cited by
218
References
128
Citations by year
2026: 30 · 2025: 50 · 2024: 54 · 2023: 54 · 2022: 18 · 2021: 8 · 2020: 4
FWCI
3.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Applied Biosafety (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Nationwide Children's Hospital
  • Research Institute, Nationwide Children's Hospital
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
viral vectors, gene therapy, biosafety, occupational health and safety, risk assessment, non-viral gene delivery, institutional biosafety committees, public trust, clinical trials

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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