Amino acid-derived dynamic oligomers for the intracellular delivery of mRNA
Abstract/Contents
- Abstract
- RNA technology is transforming life science research and medicine, however, many applications are limited by the accessibility, cost, efficacy, and tolerability of delivery systems. We recently reported a new class of gene delivery vectors with a property that makes them particularly well-suited to binding to, transporting, and releasing mRNA: charge alteration. The amphiphilic co-oligomers, synthesized via organocatalytic ring-opening polymerization (OROP), consist of a cationic oligo(N-hydroxyethyl glycine) block and readily form complexes with polyanionic mRNA. Under conditions at which the backbone is partially deprotonated, the block undergoes an irreversible depolymerization to liberate neutral small molecules. We call these materials charge-altering releasable transporters (CARTs), and they have shown remarkable efficacy in delivering mRNA in cultured cell lines and in living mice, showing a high level of protein expression localized to the spleen when administered intravenously (IV). Here, I describe two new classes of CARTs that demonstrate the versatility and tunability of this approach. I first demonstrate that the charge-altering strategy is generalizable with the development of CARTs based on oligo(serine esters). These Ser-CARTs, which rearrange to form serine-based peptides, are effective in vitro and deliver mRNA localized to the spleen. The second class is derived from the amino acid ornithine. CARTs based on oligo(N-hydroxyethyl ornithine) (O-CARTs), which contain ionizable amines on both the backbone and the side chain, perform as well or exceed the performance of previously developed CARTs in vitro. Remarkably, when administered IV, O-CART/mRNA particles show high selectivity for the lungs, and simple changes to the formulation result in a shift in the biodistribution profile to favor either splenic or systemic protein expression. These new delivery vectors demonstrate the promise of developing platform technologies in the advancement of mRNA therapies.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | McClellan, Rebecca Lane |
|---|---|
| Degree supervisor | Waymouth, Robert M |
| Thesis advisor | Waymouth, Robert M |
| Thesis advisor | Stack, T. (T. Daniel P.), 1959- |
| Thesis advisor | Xia, Yan, 1980- |
| Degree committee member | Stack, T. (T. Daniel P.), 1959- |
| Degree committee member | Xia, Yan, 1980- |
| Associated with | Stanford University, Department of Chemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Rebecca Lane McClellan. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/fn004kw9641 |
Access conditions
- Copyright
- © 2021 by Rebecca Lane McClellan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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