Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes

Parker, Alan L.; Waddington, Simon N.; Nicol, Campbell G.; Shayakhmetov, Dmitry M.; Buckley, Smk; Denby, Laura; Kemball‐Cook, Geoffrey; Ni, Shaoheng; Lieber, André; McVey, John H.; Nicklin, Stuart A.; Baker, Andrew H.

doi:10.1182/blood-2006-04-008532

Cited by 259 publications

(356 citation statements)

References 36 publications

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“…Hepatocyte transduction does not appear to be mediated by the coxsackie and adenovirus receptor, but involves either a direct or a blood factor-(coagulation factors IX and complement factors such as the complement component 4-binding protein) mediated binding. 14 In a recently proposed model, factor IX and complement component 4-binding protein bind directly to the Ad fiber and mediate the binding of Ad to alternate receptors, such as heparan sulfate proteoglycans and/ or low-density lipoprotein receptor-related protein. 15 Strategies aimed at altering the tropism of the vector to specifically target hepatocytes could take advantage of this newly recognized model of hepatocyte-Ad interaction.…”

Section: High Vector Doses Are Required For Efficient Hepatocyte Tranmentioning

confidence: 99%

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

Brunetti‐Pierri

2008

Gene Ther

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Preclinical studies in small and large animal models using helper-dependent adenoviral vectors (HDAds) have generated promising results for the treatment of genetic diseases. However, clinical translation is complicated by the dosedependent, capsid-mediated acute toxic response following systemic vector injection. With the advancements in vectorology, a better understanding of vector-mediated toxicity, and improved delivery methods, HDAds may emerge as an important vector for gene therapy of genetic diseases and this report highlights recent progress and prospects in this field.

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Section: High Vector Doses Are Required For Efficient Hepatocyte Tranmentioning

confidence: 99%

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

Brunetti‐Pierri

2008

Gene Ther

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“…[4][5][6] Several studies have documented the role of blood coagulation factors in mediating liver gene transfer in vivo and the mechanism underlying Ad5 hepatocyte transduction. [7][8][9][10][11][12] We demonstrated that coagulation factor X (FX) binds to the hexon protein of Ad5 at high affinity (B2 nM) and that this interaction mediates hepatocyte transduction following i.v. delivery in mice and rats.…”

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confidence: 99%

“…delivery in rodents, the Ad5-FX complex interacts with HSPGs on the surface of hepatocytes. 8,9,26 Recently, our group has studied the receptors used by the Ad5-FX complex in vitro and in vivo 14 in greater detail. This interaction is dependent on the sulfation of the HS chains, which interact with the serine protease domain of the FX molecule.…”

mentioning

confidence: 99%

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

et al. 2011

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Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus.

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“…Although rather complex, this mechanism is very efficient and can be specifically blocked by lactoferrin, which competes for blood factor binding to LRP and HSPGs on hepatic cells (10). It is noteworthy that, although all of these blood factors support CAR-independent cell infection by Ad5 vectors to varying degrees, coagulation factor X (FX) appears the most efficient at mediating Ad5 entry into hepatic cells in vivo (11).…”

mentioning

confidence: 99%

“…We and others recently identified a pathway of hepatocyte infection by Ad5, which is mediated by the vitamin K-dependent blood coagulation factors, including factors VII, IX, X, and protein C (10,11). When Ad5 particles are delivered intravenously, they interact with blood coagulation factors, which subsequently bind low-density lipoprotein receptor-related protein (LRP) and heparan sulfate proteoglycans (HSPGs) on hepatocytes to mediate virus entry.…”

mentioning

confidence: 99%

Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo

Kalyuzhniy

Paolo

Silvestry

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

314

373

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Human species C adenovirus serotype 5 (Ad5) is the most common viral vector used in clinical studies worldwide. Ad5 vectors infect liver cells in vivo with high efficiency via a poorly defined mechanism, which involves virus binding to vitamin K-dependent blood coagulation factors. Here, we report that the major Ad5 capsid protein, hexon, binds human coagulation factor X (FX) with an affinity of 229 pM. This affinity is 40-fold stronger than the reported affinity of Ad5 fiber for the cellular receptor coxsackievirus and adenovirus receptor, CAR. Cryoelectron microscopy and single-particle image reconstruction revealed that the FX attachment site is localized to the central depression at the top of the hexon trimer. Hexon-mutated virus bearing a large insertion in hexon showed markedly reduced FX binding in vitro and failed to deliver a transgene to hepatocytes in vivo. This study describes the mechanism of FX binding to Ad5 and demonstrates the critical role of hexon for virus infection of hepatocytes in vivo.gene transfer ͉ virus targeting

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Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes

Cited by 259 publications

References 36 publications

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo

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