Abstract:Individuals with a 1 -antitrypsin (AAT) deficiency and cystic fibrosis (CF) have a protease-antiprotease imbalance in their lungs, which leads to early onset progressive lung disease. Inhalation of AAT may restore protective levels in the lungs. This study aimed to determine the efficiency of delivering AAT using a novel inhalation device in subjects with AAT deficiency and CF compared with healthy subjects.In total, 20 subjects (six healthy, seven with AAT deficiency and seven with CF) inhaled ,70 mg of radio… Show more
“…Aerosolization is possible for a range of gene therapy delivery vectors with varying degrees of success [5], although this does require formulation development to protect vectors that are vulnerable to shear forces generated by nebulizers. Promising results have been achieved with the more gentle, vibrating mesh nebulizers, albeit to-date with protein replacement therapy rather than with a gene therapy vector [6]. 10.1080/14712598.2018.1506761-F0001Figure 1.Schematic of main cell types in the lung and liver.
(a) The lung can roughly be divided into three compartments proximally to distally: the trachea, bronchioles and alveoli.…”
Section: A Brief History Of In-vivo Gene Therapymentioning
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.
“…Aerosolization is possible for a range of gene therapy delivery vectors with varying degrees of success [5], although this does require formulation development to protect vectors that are vulnerable to shear forces generated by nebulizers. Promising results have been achieved with the more gentle, vibrating mesh nebulizers, albeit to-date with protein replacement therapy rather than with a gene therapy vector [6]. 10.1080/14712598.2018.1506761-F0001Figure 1.Schematic of main cell types in the lung and liver.
(a) The lung can roughly be divided into three compartments proximally to distally: the trachea, bronchioles and alveoli.…”
Section: A Brief History Of In-vivo Gene Therapymentioning
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.
“…A recent study has looked to improve the efficacy of AAT by addressing some of the key factors of aerosol administration such as reproducibility of delivered dosage both inter- and intra-patient and that the dose be deposited at therapeutic levels in the correct region of the lung despite differing levels of disease severity [99]. Using individually adapted breathing patterns, where both the airflow rate and inhalation were controlled for each subject, they achieved 70% total lung deposition of the AAT filling dose in all three populations studied (healthy, AAT deficient and CF) [99]. …”
Cystic Fibrosis (CF) is the most common fatal inherited disease of Caucasians, affecting about 1 in 3000 births. Patients with CF have a recessive mutation in the gene encoding the CF transmembrane conductance regulator (CFTR). CFTR is expressed in the epithelium of many organs throughout the exocrine system, however, inflammation and damage of the airways as a result of persistent progressive endobronchial infection is a central feature of CF. The inflammatory response to infection brings about a sustained recruitment of neutrophils to the site of infection. These neutrophils release various pro-inflammatory compounds including proteases, which when expressed at aberrant levels can overcome the endogenous antiprotease defence mechanisms of the lung. Unregulated, these proteases can exacerbate inflammation and result in the degradation of structural proteins and tissue damage leading to bronchiectasis and loss of respiratory function. Other host-derived and bacterial proteases may also contribute to the inflammation and lung destruction observed in the CF lung. Antiprotease strategies to dampen the excessive inflammatory response and concomitant damage to the airways remains an attractive therapeutic option for CF patients.
“…Therefore, it has been proposed that both groups of patients may benefit from 1 -PI augmentation therapy to prevent the deleterious effect of free protease (Allen, 1996;Birrer, 1995;Birrer et al, 1996) However, intravenous administration of 1 -PI did not result in a suppression of the respiratory neutrophil elastase burden (McElvaney et al, 1991). Several studies have been conducted using inhalation of an aerosolized 1 -PI in cystic fibrosis and 1 -PI deficiency Griese et al, 2001Griese et al, , 2007Martin et al, 2006;Brand et al, 2009). Whereas several studies that investigated the efficacy of treatment with an aerosolized 1 -PI both in patients with cystic fibrosis and in those with 1 -PI deficiency came to positive conclusions regarding deposition of inhaled 1 -PI in the lungs and its anti-elastase activity (see review by Siekmeier, 2010), the conclusion from other studies was that treatment with 1 -PI did not demonstrate any clinical improvements (Martin, 2006).…”
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