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Hepatology. 2015 Oct;62(4):1285-97. doi: 10.1002/hep.27936. Epub 2015 Aug 28.

Specific hepatic delivery of procollagen α1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis.

Author information

1
Institute of Translational Immunology, University of Mainz Medical Center, Mainz, Germany.
2
Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany.
3
Alnylam Pharmaceuticals, Cambridge, MA.
4
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
5
Center of Translational Oncology, Mainz, Germany.

Abstract

Fibrosis accompanies the wound-healing response to chronic liver injury and is characterized by excessive hepatic collagen accumulation dominated by collagen type I. Fibrosis often progresses to cirrhosis. Here we present in vivo evidence of an up to 90% suppression of procollagen α1(I) expression, a reduction of septa formation, and a 40%-60% decrease of collagen deposition in mice with progressive and advanced liver fibrosis that received cationic lipid nanoparticles loaded with small interfering RNA to the procollagen α1(I) gene. After intravenous injection, up to 90% of lipid nanoparticles loaded with small interfering RNA to the procollagen α1(I) gene were retained in the liver of fibrotic mice and accumulated in nonparenchymal more than parenchymal cells for prolonged periods, significantly ameliorating progression and accelerating regression of fibrosis.

CONCLUSION:

Our lipid nanoparticles loaded with small interfering RNA to the procollagen α1(I) gene specifically reduce total hepatic collagen content without detectable side effects, potentially qualifying as a therapy for fibrotic liver diseases.

PMID:
26096209
PMCID:
PMC4589454
DOI:
10.1002/hep.27936
[Indexed for MEDLINE]
Free PMC Article

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