Drug delivery agent that acts as a drug for synergistic activity
Drug delivery vehicles increase cell permeability of their cargo, but otherwise are expected to be inert. In developing a potential strategy to treat myotonic dystrophy type 1, we developed a delivery vehicle that was designed to be a direct acting drug. The oligomeric delivery agent selectively targets the expanded DNA and RNA repeat sequences (d(CTG)<sup>exp</sup> and r(CUG)<sup>exp</sup>) that cause DM1. By forming polyplexes with a locked nucleic acid CAG16 gapmer, that targets r(CUG)<sup>exp</sup>, the polyplex facilitates cellular uptake of the LNA in HeLa cells, DM1 patient myoblasts, and the skeletal muscle of DM1 mice leading to phenotypic improvements in the <i>in vitro</i> DM1 models. Although the <i>in vivo</i> results are mixed, the overall results suggest the potential of a new strategy where both drug and delivery agent actively target a disease pathology.
Authors
- Sarah Krueger (ORCID: https://orcid.org/0000-0003-4167-3730)
- Steven C. Zimmerman (ORCID: https://orcid.org/0000-0002-5333-3437)
- Philip A. Kocheril (ORCID: https://orcid.org/0000-0002-1265-5931)
- Ullas V. Chembazhi (ORCID: https://orcid.org/0000-0002-6305-3156)
- Yugang Bai (ORCID: https://orcid.org/0000-0002-9834-7517)
- Zachary Dewald
- Auinash Kalsotra (ORCID: https://orcid.org/0000-0002-1011-0006)
- Amie N. Lanzendorf (ORCID: https://orcid.org/0000-0001-9125-9840)
- Jie Chen (ORCID: https://orcid.org/0000-0001-7925-3729)
- Ke Li (ORCID: https://orcid.org/0000-0002-1115-9194)
- Dongwook Kim (ORCID: https://orcid.org/0000-0002-5496-1961)
- Junfeng Chen (ORCID: https://orcid.org/0000-0003-0007-0247)
Institutions
- Ben-Gurion University of the Negev (IL)
- University of Illinois Urbana-Champaign (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Chan Zuckerberg Biohub Chicago
- Mount St. Mary's University (US)
Publication Details
- Journal
- iScience
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1016/j.isci.2025.112890
- Citations
- 1
- Primary Topic
- Pharmacological Effects of Natural Compounds
- Type
- article
- Field-Weighted Citation Impact
- 1.56
Funders
- Muscular Dystrophy Association
- National Institutes of Health