1 option
Delivery strategies for oligonucleotide-based therapies Dora von Trentini
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- von Trentini, Dora, author.
- Language:
- English
- Subjects (All):
- Chemistry.
- Pharmacology.
- Biochemistry.
- 0485.
- 0487.
- 0419.
- Local Subjects:
- Chemistry.
- Pharmacology.
- Biochemistry.
- 0485.
- 0487.
- 0419.
- Genre:
- Academic theses
- Physical Description:
- 1 online resource (122 pages)
- Contained In:
- Dissertations Abstracts International 87-12B
- Place of Publication:
- Ann Arbor : ProQuest Dissertations and Theses, 2026
- Language Note:
- English
- Summary:
- Synthetic oligonucleotides offer a precise and elegant approach for treating disease at the gene expression level given their sequence specificity and RNA targeting capabilities. In the field of oligonucleotide therapeutics, delivery remains an ongoing challenge for both established and new targets at the organ, tissue, and subcellular localization levels. There are just over 20 FDA-approved oligonucleotide-based therapies with the majority targeting the cytoplasm or nucleus within liver or muscle cells. We present work in two avenues of delivery utilizing different strategies: the first focused on mitochondrial delivery and the second on muscular delivery for Duchenne's Muscular Dystrophy (DMD).Cytotoxicity is a major hurdle in achieving robust delivery and subsequent biological activity. Our approach to mitochondrial delivery of antisense oligonucleotides circumvents this common issue by utilizing biologically compatible exosomes found within nutrient-rich fetal bovine serum. The exosomes were characterized by their size, morphology and biomarkers; and antisense oligonucleotides targeting cytochrome c oxidase subunits I and II, containing an additional moiety for reaching the inner mitochondrial membrane, were used as their cargo. Confocal laser scanning microscopy co-localization studies, nano flow cytometry and protein knockdown studies confirmed their association and successful delivery. Treatment of numerous mitochondrial diseases and syndromes would benefit from targeted oligonucleotide delivery methods that extend beyond the cell's cytoplasmic and nuclear compartments.We also present the exploration of a novel approach for delivering phosphorodiamidate morpholino oligonucleotides (PMOs) to muscle cells as a potential treatment for DMD. The neutral charge of PMOs renders them incompatible with most transfection reagents, which are designed to be cationic for use with anionic oligonucleotides. By hybridizing a complementary linear or circular 2'-OMe RNA molecule to PMO, we aim to make the PMO compatible with a wider selection of transfection reagents for efficient cellular delivery. Circularizing the oligonucleotides via Cu(I)-catalyzed azide alkyne cycloaddition aims to assist with the dissociation of RNA and PMO within the cell. These PMOs are intended for use as utrophin upregulators, which is an alternative approach to the current DMD therapies on the market.This work demonstrates progress towards the development of various delivery modalities with potential for oligonucleotide therapeutics
- Notes:
- Source: Dissertations Abstracts International, Volume: 87-12, Section: B.
- Advisors: Dmochowski, Ivan J. Committee members: Petersson, E. James; Rhoades, Elizabeth; Kohli, Rahul
- Ph.D. University of Pennsylvania 2026
- Vendor supplied data
- Local Notes:
- School code: 0175
- ISBN:
- 9798247980360
- Access Restriction:
- Restricted for use by site license
The Penn Libraries is committed to describing library materials using current, accurate, and responsible language. If you discover outdated or inaccurate language, please fill out this feedback form to report it and suggest alternative language.