3. Evaluation of Exposure and Health Care Worker Response to Nebulized Administration of tgAAVCF to Patients With Cystic Fibrosis

Croteau, G.; Camp, John F.; Yost, M.; Heald, Ashley

doi:10.3320/1.2753430

Cited by 4 publications

(4 citation statements)

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“…All these properties of AAV have been identified by current human gene therapy trials. [11][12][13] New AAV serotypes are continuously being identified. At present, over 100 AAV variants have been isolated.…”

Section: Introductionmentioning

confidence: 99%

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

et al. 2007

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Recombinant adeno-associated (AAV) viruses have unique properties, which make them ideal vectors for gene transfer targeting the myocardium. Numerous serotypes of AAV have been identified with variable tropisms towards cardiac tissue. In the present study, we investigated the time course of expression of eight different AAV serotypes in rat myocardium and the nature of the immunity against these serotypes. We first assessed whether neutralizing antibodies (NAb) were present for any of the serotype in the rats. We injected 100 ml of each AAV 1-8 serotype (10 12 DNAse resistant particles/ml), encoding LacZ gene, into the apical wall of rat myocardium. At 1, 4, 12 and 24 weeks after gene delivery, the animals were killed and b-galactosidase (b-gal) activity was assessed by luminometry. Additionally, LacZ genomic copies and AAV capsids copies were measured through standard polymerase chain reaction analysis and cryosections from the area of viral injection were stained for X-gal detection at the same time points. No NAbs were detected against any of AAV serotypes. At all the time points studied, AAV1, 6 and 8 demonstrated the highest efficiency in transducing rat hearts in vivo. Parallel to the results with b-gal activity, the highest levels LacZ and AAV DNA genomic copies were with AAV1, 6 and 8. The positive X-gal staining depicted by these serotypes confirmed these results. These results indicate that among the various AAV serotypes, AAV1, 6 and 8 have differential tropism for the heart unaffected by pre-existing NAb in the rat. Although AAV 1 and 6 vectors induced rapid and robust expression and reach a plateau at 4 weeks, AAV 8 continued increasing until the end of the study. AAV 2, 5 and 7 vectors were slower to induce expression of the reporter gene, but did reach levels of expression comparable to AAV1 and AAV6 vectors after 3 months. Gene Therapy (2007) 14, 989-997.

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Section: Introductionmentioning

confidence: 99%

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

et al. 2007

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“…Caregivers and family members are susceptible to unintended inhalation of medication. In the occupational setting, studies have highlighted concerns regarding secondary exposure to aerosolised sustained release lipid inhalation targeting (SLIT) cisplatin, pentamidine, adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator complementary DNA (tgAAVCF) and ribavirin [16][17][18][19]. Additionally, after entering the profession, respiratory therapists are reported to have an increased risk of developing asthma, which, in part, may be due to exposure to a range of aerosolised substances in the clinical setting [20,21].To date, only a limited number of studies have examined the potential for fugitive releases during aerosol therapy.…”

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confidence: 99%

Investigation of Fugitive Aerosols Released into the Environment during High-Flow Therapy

et al. 2019

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Background: Nebulised medical aerosols are designed to deliver drugs to the lungs to aid in the treatment of respiratory diseases. However, an unintended consequence is the potential for fugitive emissions during patient treatment, which may pose a risk factor in both clinical and homecare settings. Methods: The current study examined the potential for fugitive emissions, using albuterol sulphate as a tracer aerosol during high-flow therapy. A nasal cannula was connected to a head model or alternatively, a interface was connected to a tracheostomy tube in combination with a simulated adult and paediatric breathing profile. Two aerodynamic particle sizers (APS) recorded time-series aerosol concentrations and size distributions at two different distances relative to the simulated patient. Results: The results showed that the quantity and characteristics of the fugitive emissions were influenced by the interface type, patient type and supplemental gas-flow rate. There was a trend in the adult scenarios; as the flow rate increased, the fugitive emissions and the mass median aerodynamic diameter (MMAD) of the aerosol both decreased. The fugitive emissions were comparable when using the adult breathing profiles for the nasal cannula and tracheostomy interfaces; however, there was a noticeable distinction between the two interfaces when compared for the paediatric breathing profiles. The highest recorded aerosol concentration was 0.370 ± 0.046 mg m−3 from the tracheostomy interface during simulated paediatric breathing with a gas-flow rate of 20 L/min. The averaged MMAD across all combinations ranged from 1.248 to 1.793 µm by the APS at a distance of 0.8 m away from the patient interface. Conclusions: Overall, the results highlight the potential for secondary inhalation of fugitive emissions released during simulated aerosol treatment with concurrent high-flow therapy. The findings will help in developing policy and best practice for risk mitigation from fugitive emissions.

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“…There are also phase I human trials for ∝1-anti-trypsin deficiency [ 29 ], Canavan disease [ 30 - 32 ], infantile neuronal ceroid lipofuscinosis [ 33 ] and Parkinson disease [ 34 ]. The only two phase II clinical trials already published were directed to cystic fibrosis [ 35 , 36 ]. At least 20 clinical trials have been completed or initiated with 15 different AAV2-based vectors being administered in several hundred patients [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

The state of the art of adeno-associated virus-based vectors in gene therapy

2007

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The adeno-associated virus (AAV) has rapidly gained popularity in gene therapy since the establishment of the first AAV2 infectious clone, in 1982, due to some of their distinguishing characteristics such as lack of pathogenicity, wide range of infectivity, and ability to establish longterm transgene expression. Notably over the past decade, this virus has attracted considerable interest as a gene therapy vector, and about 85% of the currently available 2,041 PubMed references on adeno-associated viruses have been published during this time. The exponential progress of AAV-based vectors has been made possible by the advances in the knowledge of the virology and biology of this virus, which allows great improvement in AAV vectors construction and a better comprehension of their operation. Moreover, with the recent discovery of novel AAV serotypes, there is virtually one preferred serotype for nearly every organ or tissue to target. Thus, AAV-based vectors have been successfully overcoming the main gene therapy challenges such as transgene maintenance, safety and host immune response, and meeting the desirable vector system features of high level of safety combined with clinical efficacy and versatility in terms of potential applications. Consequently, AAV is increasingly becoming the vector of choice for a wide range of gene therapy approaches. This report will highlight the state of the art of AAV-based vectors studies and the advances on the use of AAV vectors for several gene therapy approaches.

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3. Evaluation of Exposure and Health Care Worker Response to Nebulized Administration of tgAAVCF to Patients With Cystic Fibrosis

Cited by 4 publications

References 0 publications

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo

Investigation of Fugitive Aerosols Released into the Environment during High-Flow Therapy

The state of the art of adeno-associated virus-based vectors in gene therapy

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