Carolina Jiménez Calvente1,2, Alfica Sehgal3, Yury Popov4, Yong Ook Kim1,2, Victor Zevallos1,2, Ugur Sahin2,5, Mustafa Diken2,5, Detlef Schuppan1,2,4. 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
UNLABELLED: 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.
UNLABELLED: 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.
Authors: Kevin T Love; Kerry P Mahon; Christopher G Levins; Kathryn A Whitehead; William Querbes; J Robert Dorkin; June Qin; William Cantley; Liu Liang Qin; Timothy Racie; Maria Frank-Kamenetsky; Ka Ning Yip; Rene Alvarez; Dinah W Y Sah; Antonin de Fougerolles; Kevin Fitzgerald; Victor Koteliansky; Akin Akinc; Robert Langer; Daniel G Anderson Journal: Proc Natl Acad Sci U S A Date: 2010-01-11 Impact factor: 11.205
Authors: T Rogalla; M Ehrnsperger; X Preville; A Kotlyarov; G Lutsch; C Ducasse; C Paul; M Wieske; A P Arrigo; J Buchner; M Gaestel Journal: J Biol Chem Date: 1999-07-02 Impact factor: 5.157