Transduction of Liver Metastases After Intravenous Injection of Ad5/35 or Ad35 Vectors With and Without Factor X-Binding Protein Pretreatment

Liu, Ying; Wang, Hongjie; Yumul, Roma; Gao, Wentao; Gambotto, Andrea; Morita, Takashi; Baker, Andrew H.; Shayakhmetov, Dmitry M.; Lieber, André

doi:10.1089/hum.2008.142

Cited by 21 publications

(27 citation statements)

References 26 publications

(25 reference statements)

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“…Vector genomes were detected in the lung, liver, heart, kidney, and spleen at levels between 5 and 20 genome copies per cell ( Figure 5A). [26][27][28] Vector DNA levels in the gastrointestinal tract and ovaries were 2 orders of magnitude lower. We speculate that the vector PCR signals in the lung, liver, kidney, and spleen reflect transduced leukocytes either as part of residual blood or as tissue infiltrates.…”

Section: Safety Of IV Hd-ad5/35 11 Vector Injectionmentioning

confidence: 99%

“…Previously, we and others have shown that Ad5 entry into hepatocytes is mediated by Ad5 hexon protein interaction with coagulation FX 26,27 and that this pathway is inefficient if Ad5 vectors contain the short Ad35 fibers (such as in the Ad5/35 11 vectors used here), most likely due to a steric block of the FX-interacting domains within the Ad5 hexon. 28 (C) Levels of serum alanine transaminase and aspartate transaminase at day 3 after Ad injection. N 5 3.…”

Section: In Vivo Hspc Transduction In Humanized Micementioning

confidence: 99%

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In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

Richter

Saydaminova

Yumul

et al. 2016

Blood

Self Cite

145

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• Mobilized hematopoietic stem cells transduced with IV injected HD-Ad5/35 11 vectors home to the BM persist long term.• Our approach allows for the stable genetic modification of primitive, long-term persisting HSPCs.Current protocols for hematopoietic stem/progenitor cell (HSPC) gene therapy, involving the transplantation of ex vivo genetically modified HSPCs are complex and not without risk for the patient. We developed a new approach for in vivo HSPC transduction that does not require myeloablation and transplantation. It involves subcutaneous injections of granulocyte-colony-stimulating factor/AMD3100 to mobilize HSPCs from the bone marrow (BM) into the peripheral blood stream and the IV injection of an integrating, helper-dependent adenovirus (HD-Ad5/35 11 ) vector system. These vectors target CD46, a receptor that is uniformly expressed on HSPCs. We demonstrated in human CD46 transgenic mice and immunodeficient mice with engrafted human CD34 1 cells that HSPCs transduced in the periphery home back to the BM where they stably express the transgene. In hCD46 transgenic mice, we showed that our in vivo HSPC transduction approach allows for the stable transduction of primitive HSPCs. Twenty weeks after in vivo transduction, green fluorescent protein (GFP) marking in BM HSPCs (Lin 2 Sca1 1 Kit 2 cells) in most of the mice was in the range of 5% to 10%. The percentage of GFP-expressing primitive HSPCs capable of forming multilineage progenitor colonies (colony-forming units [CFUs]) increased from 4% of all CFUs at week 4 to 16% at week 12, indicating transduction and expansion of long-term surviving HSPCs. Our approach was well tolerated, did not result in significant transduction of nonhematopoietic tissues, and was not associated with genotoxicty. The ability to stably genetically modify HSPCs without the need of myeloablative conditioning is relevant for a broader clinical application of gene therapy. (Blood. 2016;128(18):2206-2217

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Section: Safety Of IV Hd-ad5/35 11 Vector Injectionmentioning

confidence: 99%

Section: In Vivo Hspc Transduction In Humanized Micementioning

confidence: 99%

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

Richter

Saydaminova

Yumul

et al. 2016

Blood

Self Cite

145

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“…Approaches using Ad5/35 have had varied tumor targeting efficacy in vivo , with reports of low level transduction of breast and liver metastases [237,239,241]. However, delivery of Ad5/35 to liver metastases was improved using a snake venom FX-binding protein (X-bp), to inhibit the Ad5 association with coagulation FX [237].…”

Section: Retargeting Adenoviral Vectorsmentioning

confidence: 99%

Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors

Coughlan

Alba

Parker

et al. 2010

Viruses

103

100

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Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications.

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“…While promising, it is impractical to incorporate the bridging molecule into an OAd system because effective incorporation of bridging molecules into progeny viruses is not easy [17]. In recognition of this fact, chimeric fiber approaches such as Ad5 / 3 (Ad5 vectors with the fiber knob domain of Ad3) are more frequently applied for OAds and chimeric OAds displays improved gene delivery and antitumor efficacy in many preclinical studies [18,28,34–36]. Additionally, ColoAd1 (also known as enadenotucirev, EnAd), a complex and highly potent chimeric Ad3/Ad11p virus, was generated by a novel “directed evolution” approach for its ability to kill colorectal cancer cells[37].…”

Section: Adenoviral Transductional Targeting and Its Application Tmentioning

confidence: 99%

The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer

Sato-Dahlman

Yamamoto

2018

CCDT

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Pancreatic cancer is an aggressive malignant disease and the efficacy of current treatments for unresectable diseases is quite limited despite recent advances. Gene therapy/virotherapy strategies may provide new options for treatment of various cancers including pancreatic cancer. Oncolytic adenovirus shows an antitumoral effect via its intratumoral amplification and strong cytocidal effect in a variety of cancers and it has been employed for the development of potent oncolytic virotherapy agents for pancreatic cancer. Our ultimate goal is to develop an oncolytic adenovirus enabling treatment of patients with advanced or spread diseases by systemic injection. Systemic application of oncolytic therapy mandates more efficient and selective gene delivery and needs to embody sufficient antitumor effect even with limited initial delivery to the tumor location. In this review, the current status of oncolytic adenoviruses from the viewpoints of vector design and potential strategies to overcome current obstacles for its clinical application will be described. We will also discuss the efforts to improve the antitumor activity of oncolytic adenovirus, in in vivo animal models, and the combination therapy of oncolytic adenovirus with radiation and chemotherapy.

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Transduction of Liver Metastases After Intravenous Injection of Ad5/35 or Ad35 Vectors With and Without Factor X-Binding Protein Pretreatment

Cited by 21 publications

References 26 publications

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors

The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer

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