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Advances in gene therapy for respiratory diseases 2

Part 2 of 2
Published on November 30, 2023   41 min

Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms

Other Talks in the Series: Gene Transfer and Gene Therapy

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Welcome to Part 2, Advances in Gene Therapy for Respiratory Diseases.
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Now, I'd like to move into discussion of viral vectors that can be used for gene therapy of cystic fibrosis. Adeno-associated virus, as shown here, is a very simple single-stranded DNA genome vector that has a good safety profile in human clinical trials, it transduces both dividing and non-dividing cells, which is attractive for the airway. There are many serotypes that exist. There's persistent expression of the transgene as an episome, although if cells divide, it's diluted with cell division because there is minimal integration. The virus can be produced at high yields for both research and GMP grade. The disadvantages include the small packaging size, which is limited to about 4.9 kb maximum and at least for airway applications there were significant intercellular block in transport to the nucleus that occurs, which involves the ubiquitination and the proteasome, which I'll discuss briefly.
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Now, adeno-associated viral vectors are fairly simple. The wild type genome, shown here, contains two genes. A 'rep' gene composed of replication proteins that encoded by those mRNA transcripts and the 'cap' gene that encodes the capsid proteins. These are flanked by two inverted terminal repeats that are involved in the replication of the viral genome. Now, a recombinant adeno-associated virus removes all these viral genes and replace it with a recombinant cDNA in this particular KDR. Now, there are many serotypes of AAV that exist, making it attractive to screen and find vector systems that can transduce the appropriate cells in the lung, and directed evolution is a process in which the shuffling of capsid genes can be performed in libraries made that can be screened for very selective tropisms to cell types using panning techniques.
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Advances in gene therapy for respiratory diseases 2

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