Impact of liver fibrosis on AAV-mediated gene transfer to mouse hepatocytes

被引：1

作者：

Ferriero, Rosa ^{[1
]}

Bruno, Gemma ^{[1
]}

Padula, Agnese ^{[1
]}

Pisano, Simone ^{[1
,2
]}

Boffa, Iolanda ^{[1
]}

Gargaro, Marco ^{[3
]}

Imperatore, Teresa ^{[1
,4
]}

Battipaglia, Maria ^{[1
,2
]}

Vivenzio, Silvia ^{[1
]}

Perna, Claudia ^{[1
]}

Nusco, Edoardo ^{[1
]}

Ferrante, Luigi ^{[1
]}

Westhaus, Adrian ^{[5
,11
]}

Knight, Maddison ^{[5
]}

Manni, Giorgia ^{[3
]}

Campione, Severo ^{[6
]}

Di Napoli, Evaristo ^{[7
]}

Polishchuk, Elena ^{[1
]}

Polishchuk, Roman ^{[1
]}

Paciello, Orlando ^{[7
]}

Brunetti-Pierri, Nicola ^{[1
,4
,8
]}

Lisowski, Leszek ^{[5
,9
,10
]}

Fallarino, Francesca ^{[3
]}

Piccolo, Pasquale ^{[1
]}

机构：

[1] Telethon Inst Genet & Med TIGEM, Pozzuoli, Italy

[2] European Sch Mol Med SEMM, Milan, Italy

[3] Univ Perugia, Dept Med & Surg, Perugia, Italy

[4] Sch Adv Studies, Scuola Super Meridionale, Genom & Expt Med Program, SSM, Naples, Italy

[5] Univ Sydney, Childrens Med Res Inst, Fac Med & Hlth, Translat Vectorol Res Unit, Westmead, NSW, Australia

[6] Cardarelli Hosp, Pathol Unit, Naples, Italy

[7] Feder II Univ Naples, Dept Vet Med & Anim Prod, Naples, Italy

[8] Federico II Univ Naples, Dept Translat Med, Naples, Italy

[9] Sydney Childrens Hosp Network, Childrens Med Res Inst, Australian Genome Therapeut Ctr, Westmead, NSW, Australia

[10] Mil Inst Med Natl Res Inst, Lab Mol Oncol & Innovat Therapies, Warsaw, Poland

[11] INSERM, Integrare Res Unit, UMR S951, Evry, France

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

关键词：

ADENOASSOCIATED VIRAL VECTORS; COPPER ACCUMULATION; IMMUNE-RESPONSES; STELLATE CELLS; MURINE LIVER; IN-VITRO; TRANSDUCTION; RECEPTOR; DISEASE; ABCB4;

D O I：

10.1038/s41467-025-57382-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Liver fibrosis, characterized by scar tissue accumulation due to liver injury, poses significant barriers to liver-targeted gene therapy. Current clinical trials exclude patients with fibrosis, as intact liver architecture is considered essential for efficient and safe adeno-associated viral vector (AAV)-mediated gene delivery. Here, we show that liver fibrosis reduces the efficiency of hepatocyte transduction by AAV8 vectors across three mouse models with diverse fibrotic patterns. This inefficiency stems primarily from decreased vector uptake by the liver rather than loss of vector genomes due to hepatocyte turnover. Additionally, fibrosis alters blood vector clearance and redistributes AAV particles to extra-hepatic organs, such as spleen, lung, and kidney. At the cellular level, fibrosis decreases AAV genome content in hepatocytes while increasing it in non-parenchymal liver cells and splenic immune cells. Importantly, the capsid variant AAV-KP1 retains transduction efficiency in fibrotic livers, highlighting its potential for expanding gene therapy applications to fibrotic diseases.

引用

页数：13

共 57 条

[1] The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9 [J].