An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy

Duncan, Gregg A.; Kim, Nam-Ho; Colon-Cortes, Yanerys; Rodriguez, Jason; Mazur, Marina; Birket, Susan E.; Rowe, Steven M.; West, Natalie E.; Livraghi‐Butrico, Alessandra; Boucher, Richard C.; Hanes, Justin; Aslanidi, George; Suk, Jung Soo

doi:10.1016/j.omtm.2018.03.006

Cited by 47 publications

(41 citation statements)

References 55 publications

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“…It remains nevertheless unclear how many CFTR modulators would be needed to reach such threshold in patients. In addition to CFTR modulators, progress has been made in developing cell-based (Barical et al, 2019;Hayes et al, 2019) and gene-based therapies (Donnelley and Parsons, 2018;Duncan et al, 2018;Lopes-Pacheco et al, 2018;Osman et al, 2018) for CF lung disease.…”

Section: Continuing the Development Of Transformative Therapeutics Tomentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Continuing the Development Of Transformative Therapeutics Tomentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…AAV6 vectors and their modifications have shown to be effective in lung gene transfer of healthy ( Halbert et al, 2010 ; Kurosaki et al, 2017 ; Kurosaki et al, 2018 ; van Lieshout et al, 2018 ; Strobel et al, 2015 ), mucus-covered/plugged airways of Scnn1b-Tg mice ( Duncan et al, 2018 ) and dogs ( Halbert et al, 2010 ). More importantly, they have higher efficiency in transducing human AE cell lines and primary cells in the air-liquid interface (ALI) cultures ( Kurosaki et al, 2017 ; Duncan et al, 2018 ; Song et al, 2009 ; Limberis et al, 2009 ). We also showed superior penetration of the AAV6 vectors in freshly isolated human mucus ( Duncan et al, 2018 ) in comparison to other clinically relevant AAV serotypes ( Schuster et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Intra-tracheal delivery of AAV6 vectors results in sustained transduction in murine lungs without genomic integration

Colon-Cortes

Hasan

Aslanidi

2020

Gene

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Despite the progress made in AAV-based gene therapy targeting different organ systems, lung-targeted gene therapy using AAV vectors has not been effective, mostly due to the poor transduction and un-sustained gene expression in airway epithelium. Furthermore, concerns over possible harmful insertional mutagenesis seen in other cell types, particularly hepatocytes, raised a question about AAV safety. In this study, we evaluate the long-term persistence of this vector in mouse lungs and any possible harmful integration of these vectors into the host genome. AAV6 vectors expressing reporter gene (firefly luciferase) were delivered to the lungs of C57BL/6 mice through intra-tracheal intubation. Despite the large variation among individual animals, most animals had high and sustained luciferase activity with a peak from 2 to 3 weeks post-transduction before a significant decline between 15 and 19 weeks post-transduction. More importantly, even after its decline, most animals maintained detectable luciferase expression for 150 days or more, which was confirmed by post-necropsy qPCR analysis of luciferase gene expression. At the termination point of experiments, an average of one copy of AAV expression cassette per mouse genome was detected. We also found that partial overlaps between the AAV6 expression cassette and the mouse genome were distributed broadly with no apparent systematic preference in any mouse chromosomal map location. In summary, our data suggest that AAV6 mediated long-term gene expression in the lungs with no evidence of genomic integration, and thus, any insertional mutagenesis.

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“…Only a small fraction of rAAV particles could penetrate CF mucus to reach airway epithelia, and thus it is perhaps not surprising that modulation of CF mucus viscosity with a mucolytic drug (N-acetylcysteine) improved rAAV1 vector diffusion. Further to this, alternative AAV vector serotypes, particularly serotype 6 [90], was identified as capable of rapidly diffusing through CF mucus compared with AAV1 capsid. Recombinant AAV vectors based on serotype 2 were principally used in previous clinical trials [54,55,56], and its reduced ability to transverse CF mucus at the airway liquid surface interface may, in part, explain the disappointing outcomes.…”

Section: Improving Rad and Raav Vectors For Cf Gene Therapymentioning

confidence: 91%

Emerging gene therapies for cystic fibrosis

Miah

Hyde

Gill

2019

Expert Review of Respiratory Medicine

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Introduction: Cystic Fibrosis (CF) remains a life-threatening genetic disease, with few clinically effective treatment options. Gene therapy and gene editing strategies offer the potential for a one-time CF cure, irrespective of the CFTR mutation class. Areas covered: We review emerging gene therapies and gene delivery strategies for the treatment of CF particularly viral and non-viral approaches with potential to treat CF. Expert opinion: It was initially anticipated that the challenge of developing a gene therapy for CF lung disease would be met relatively easily. Following early proof-of-concept clinical studies, CF gene therapy has entered a new era with innovative vector designs, approaches to subvert the humoral immune system and increase gene delivery and gene correction efficiencies. Developments include integrating Adenoviral vectors, Rapamycin loaded nanoparticles and lung-tropic lentiviral vectors. The characterisation of novel cell types in the lung epithelium, including pulmonary ionocytes, may also encourage cell type-specific targeting for CF correction. We anticipate preclinical studies to further validate these strategies, which should pave the way for clinical trials. We also expect gene editing efficiencies to improve to clinically translatable levels, given advancements in viral and nonviral vectors. Overall, gene delivery technologies look more convincing in producing an effective CF gene therapy.

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An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy

Cited by 47 publications

References 55 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Intra-tracheal delivery of AAV6 vectors results in sustained transduction in murine lungs without genomic integration

Emerging gene therapies for cystic fibrosis

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