Immunological Ignorance Allows Long-Term Gene Expression After Perinatal Recombinant Adeno-Associated Virus-Mediated Gene Transfer to Murine Airways

Carlon, Marianne; Vidovic, Dragana; Dooley, James; Cunha, Marina Gabriela Monteiro Carvalho Mori da; Maris, Michael; Lampi, Youlia; Toelen, Jaan; Haute, Chris Van den; Baekelandt, Veerle; Deprest, Jan; Verbeken, Erik; Liston, Adrian; Gijsbers, Rik; Debyser, Zeger

doi:10.1089/hum.2013.196

Cited by 17 publications

(17 citation statements)

References 54 publications

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“…There is however no evidence for tolerance induction against the viral vector itself, probably due to the limited half‐life of the viral proteins once injected into the body . Furthermore, we have learnt from fetal gene therapy studies in mice that vector delivery to an immature immune system allows a single repeated administration due to immunological ignorance against the rAAV capsid, but that later readministrations are hampered by anti‐capsid neutralizing antibodies . Translation to humans however remains to be investigated.…”

Section: An Early Intervention To Prevent Progressive Lung Diseasementioning

confidence: 99%

“…109 Furthermore, we have learnt from fetal gene therapy studies in mice that vector delivery to an immature immune system allows a single repeated administration due to immunological ignorance against the rAAV capsid, but that later readministrations are hampered by anticapsid neutralizing antibodies. [112][113][114] Translation to humans however remains to be investigated.…”

Section: An Early Intervention To Prevent Progressive Lung Diseasementioning

confidence: 99%

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Roadmap for an early gene therapy for cystic fibrosis airway disease

2017

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Gene therapy provides a mutation-independent approach to treat or even cure CF airway disease. To develop a clinical candidate for CF gene therapy, a thorough examination of preclinical efficacy in relevant cell and animal models is a prerequisite. For a long time, the CF field was struggling with a lack of appropriate animal models for CF airway pathology. Since 2008, many different and complementary animal models have been generated that develop hallmarks of CF airway disease, including the CF pig, ferret, and rat. With this, a new era has arisen that allows investigating the efficacy of gene therapy beyond molecular and electrophysiological end-points. Successful gene therapy most likely requires an appropriate time window. CF lung pathology progresses with age and therefore an early treatment would be beneficial to prevent irreversible damage. In that regard, newborn screening programs and prenatal diagnosis already provide a basis to facilitate future preventive gene-based treatment. If successful, gene therapy for CF airway disease would markedly reduce the treatment burden and improve life quality and life expectancy of CF patients.

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Section: An Early Intervention To Prevent Progressive Lung Diseasementioning

confidence: 99%

Section: An Early Intervention To Prevent Progressive Lung Diseasementioning

confidence: 99%

Roadmap for an early gene therapy for cystic fibrosis airway disease

2017

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“…This is particularly important if repetitive administration, which induces an immune response and decreases efficiency through neutralizing antibodies, is required (45,46). This limitation could be overcome by the delivery of gene-editing reagents early in life before exposure to natural infection and when the immune system is still immature (47). Therapeutic intervention in the fetal period may induce immune tolerance and improve efficiency.…”

Section: Crispr As a Therapeutic Strategymentioning

confidence: 99%

Gene Editing and Genetic Lung Disease. Basic Research Meets Therapeutic Application

Alapati

Morrisey

2017

Am J Respir Cell Mol Biol

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Although our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin deficiency is extensive, treatment options are lacking. Because the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intratracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene-editing technology is a promising approach to repairing or inactivating disease-causing mutations. Recent reports have provided proof of concept by using CRISPR/Cas9 to successfully repair or inactivate mutations in animal models of monogenic human diseases. Potential pulmonary applications of CRISPR/Cas9 gene editing include gene correction of monogenic diseases in pre-or postnatal lungs and ex vivo gene editing of patient-specific airway stem cells followed by autologous cell transplant. Strategies to enhance gene-editing efficiency and eliminate off-target effects by targeting pulmonary stem/progenitor cells and the assessment of short-term and long-term effects of gene editing are important considerations as the field advances. If methods continue to advance rapidly, CRISPR/Cas9-mediated gene editing may provide a novel opportunity to correct monogenic diseases of the respiratory system.

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“…In choosing a viral vector as the mode of delivery, the adeno‐associated virus (AAV) has been suggested as an alternative to lentiviral vectors, due to both its decreased risk of mutagenesis relative to lentiviral vectors and its low host immunogenicity resulting in longer lasting gene expression relative to adenoviral vectors (Mitchell et al, ; Keswani et al, ; Carlon et al, ; Schuster et al, ). While AAV vector‐mediated gene therapy provides relatively long‐lasting gene expression compared to lentiviral therapies, currently a sizeable portion of CF gene therapy occurs postnatally, presenting several difficulties in the transduction of a functional CFTR gene (Keswani et al, ).…”

Section: Adeno‐associated Viral Vectors In the Postnatal Environmentmentioning

confidence: 99%

Cystic fibrosis: A look into the future of prenatal screening and therapy

Nishida

Smith

Rana

et al. 2015

Birth Defects Research Pt C

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Despite recent guidelines suggesting prenatal screening for carriers of cystic fibrosis (CF) mutations, many physicians do not offer patients this service or even counseling. Some argue that the risks of miscarriage associated with prenatal diagnostic techniques outweigh the benefit of added insight, but with the advent of newer, noninvasive techniques, risks of miscarriage may be significantly lowered. Prenatal diagnosis provides parents the time to prepare for raising a child with CF, and soon, could provide treatment options in utero that could improve quality of life. Here, we describe two of the most promising gene therapy approaches: lentivirus and adenoassociated virus (AAV)-mediated gene transduction. Thus, prenatal detection and treatment is in a most crucial stage for care of patients with CF.

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Immunological Ignorance Allows Long-Term Gene Expression After Perinatal Recombinant Adeno-Associated Virus-Mediated Gene Transfer to Murine Airways

Cited by 17 publications

References 54 publications

Roadmap for an early gene therapy for cystic fibrosis airway disease

Roadmap for an early gene therapy for cystic fibrosis airway disease

Gene Editing and Genetic Lung Disease. Basic Research Meets Therapeutic Application

Cystic fibrosis: A look into the future of prenatal screening and therapy

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