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Reprogramming the Retina: Next Generation Strategies of Retinal Neuroprotection and Gene Therapy Vector Potency Assessment / Devin S. McDougald.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- McDougald, Devin S., author.
- Language:
- English
- Subjects (All):
- Molecular biology.
- Genetics.
- Virology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Local Subjects:
- Molecular biology.
- Genetics.
- Virology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (140 pages)
- Contained In:
- Dissertations Abstracts International 80-07B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2018.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Mutations within over 250 known genes are associated with inherited retinal degeneration. Clinical success following gene replacement therapy for Leber's congenital amaurosis type 2 establishes a platform for the development of downstream treatments targeting other forms of inherited and acquired ocular disease. Unfortunately, several challenges relevant to complex disease pathology and limitations of current gene transfer technologies impede the development of gene replacement for each specific form of retinal degeneration. Here we describe gene augmentation strategies mediated by recombinant AAV vectors that impede retinal degeneration in pre-clinical models of acquired and inherited vision loss. We demonstrate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis following AAV-mediated gene augmentation. Gene transfer of the antioxidant transcription factor, NRF2, improves RGC survival while overexpression of the pro-survival and anti-inflammatory protein, SIRT1, promotes preservation of visual function. In the context of inherited retinal disease, we show stimulation of anabolic metabolism following AKT3 gene transfer preserves photoreceptor viability and delays functional loss in a mouse model of retinitis pigmentosa. In addition to these neuroprotective strategies, we also describe an approach to improve the in vitro potency of AAV vectors that are restricted by tissue-specific regulatory elements. This strategy utilizes genome engineering based on CRISPR/Cas9 gene activation to reprogram cell lines to specifically and potently express tissue-specific promoters of interest from AAV vectors.
- Notes:
- Source: Dissertations Abstracts International, Volume: 80-07, Section: B.
- Publisher info.: Dissertation/Thesis.
- Advisors: Bennett, Jean; Committee members: Valder Arruda; Claire Mitchell; Kenneth Shindler; Hansell Stedman.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2018.
- Local Notes:
- School code: 0175
- ISBN:
- 9780438766945
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
- This item must not be added to any third party search indexes.
- This item must not be sold to any third party vendors.
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