Adeno-associated virus-based gene therapy for treating lung surfactant deficiencies

dc.contributor.advisorWootton, Sarah
dc.contributor.authorDomm, Jakob Matthias
dc.date.accessioned2018-07-25T19:11:57Z
dc.date.available2019-07-20T05:00:33Z
dc.date.copyright2018-07
dc.date.created2018-07-20
dc.date.issued2018-07-25
dc.degree.departmentDepartment of Pathobiologyen_US
dc.degree.grantorUniversity of Guelphen_US
dc.degree.nameMaster of Scienceen_US
dc.degree.programmePathobiologyen_US
dc.description.abstractMonogenic lung surfactant deficiencies are fatal and lead to death in neonates within a year of life unless they receive a lung transplant. Deficiencies such as Surfactant protein-B (SP-B) deficiency or ATP-binding cassette subfamily A member 3 (ABCA3) deficiency lead to decreased functionality of lung surfactant, atelectasis, and severe respiratory distress. We investigated three different strategies to deliver therapeutic transgenes for transient expression to prolong life, or integrate corrective genes to cure the disorder. The first method utilized a single AAV6.2FF vector to deliver SP-B cDNA to a deficient mouse model and we observed an extension of survival. The second method employed a split-vector system to deliver both halves of ABCA3 cDNA separately to recombine in vivo, and was found to result in efficient expression of full length ABCA3 in the distal airways of mice. Thirdly, we developed an AAV6.2FF- mediated CRISPR/Cas9 gene-editing platform that caused efficient insertion and expression of promoterless transgenes in dividing alveolar type II cells. Together, these findings show efficacy of AAV-based gene therapy options to either extend life, or replace a gene in dividing cells to correct lung surfactant deficiency.en_US
dc.description.sponsorshipOntario Veterinary College Stipend
dc.description.sponsorshipThe University of Guelph Graduate Entrance Excellence Scholarship
dc.description.sponsorshipCanadian Institutes of Health Research
dc.description.sponsorshipOntario Lung Association
dc.description.sponsorshipCystic Fibrosis Canada
dc.identifier.urihttp://hdl.handle.net/10214/14055
dc.language.isoenen_US
dc.publisherUniversity of Guelphen_US
dc.rightsAttribution 2.5 Canada*
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/ca/*
dc.subjectAAVen_US
dc.subjectAdeno-associated virusen_US
dc.subjectgene therapyen_US
dc.subjectgene editingen_US
dc.subjectCRISPR/CAS9en_US
dc.subjectSaCas9en_US
dc.subjectlungen_US
dc.subjectpulmonaryen_US
dc.subjectlung gene therapyen_US
dc.subjectAAV6.2FFen_US
dc.subjectSP-Ben_US
dc.subjectSurfactant Protein Ben_US
dc.subjectABCA3en_US
dc.subjectsurfactant deficienciesen_US
dc.subjectsurfactant dysfunctionen_US
dc.subjectnewborn diseaseen_US
dc.subjectrespiratory disease syndromeen_US
dc.subjectinfantile diseaseen_US
dc.subjectgenetic diseaseen_US
dc.subjectgenetic disorderen_US
dc.titleAdeno-associated virus-based gene therapy for treating lung surfactant deficienciesen_US
dc.typeThesisen_US

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