Journal
MOLECULAR THERAPY
Volume 27, Issue 3, Pages 493-506Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2019.01.003
Keywords
-
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK074867]
- NIDDK [R01 DK109717]
- Office of Dietary Supplements
- China Scholarship Council
- Crohn's & Colitis Foundation of America
- Department of Veteran Affairs
Ask authors/readers for more resources
Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1 (Dmt1) would attenuate iron loading in a mouse model of hereditary hemochromatosis (HH). Initial experiments using duodenal epithelial organ cultures from intestine-specific Dmt1 knockout (KO) (Dmt1(int/int)) mice in the Ussing chamber established that Dmt1 is the only active iron importer during iron-deficiency anemia. Further, when Dmt1(int/int) mice were crossed with mice lacking the iron-regulatory hormone, hepcidin (Hepc(-/-)), iron loading was abolished. Hence, intestinal Dmt1 is required for the excessive iron absorption that typifies HH. Additional experiments established a protocol to produce GDLVs carrying functional Dmt1 small interfering RNAs (siRNAs) and to target these gene delivery vehicles to the duodenal epithelium in vivo (by incorporating folic acid [FA]). When FA-GDLVs carrying Dmt1 siRNA were administered to weanling Hepc(-/-) mice for 16 days, intestinal Dmt1 mRNA expression was attenuated and tissue iron accumulation was blunted. Oral delivery of functional siRNAs by FA-GDLVs is a suitable therapeutic approach to mitigate iron loading in murine HH.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available