Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders

Cavalieri, Vincenzo; Baiamonte, Elena; Iacono, Melania Lo

doi:10.3390/v10060316

Cited by 26 publications

(14 citation statements)

References 150 publications

(144 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…A non-primate LV vector system based on equine infectious anemia virus (EIAV) has been investigated clinically to treat ocular disorders. 38 In another in vivo application, an HIV-1-based, integra-tion-deficient LV vector expressing the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) cancer testis antigen and targeted to dendritic cells was used to promote an immune response against NY-ESO-1-expressing tumors. 39 In vivo gene-therapy approaches involving LV vectors have faced a number of challenges, including efficiency of transgene delivery; a need for tissue-restricted transgene expression; immunogenicity to both the product encoded by the transgene as well as components of the vector, including its envelope; and inactivation by the human complement cascade.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In vivo targeting of lentiviral vectors pseudotyped with the Tupaia paramyxovirus H glycoprotein bearing a cell-specific ligand

Argaw

Marino

Timmons

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Despite their exceptional capacity for transgene delivery ex vivo , lentiviral (LV) vectors have been slow to demonstrate clinical utility in the context of in vivo applications. Unresolved safety concerns related to broad LV vector tropism have limited LV vectors to ex vivo applications. Here, we report on a novel LV vector-pseudotyping strategy involving envelope glycoproteins of Tupaia paramyxovirus (TPMV) engineered to specifically target human cell-surface receptors. LV vectors pseudotyped with the TPMV hemagglutinin (H) protein bearing the interleukin (IL)-13 ligand in concert with the TPMV fusion (F) protein allowed efficient transduction of cells expressing the human IL-13 receptor alpha 2 (IL-13Rα2). Immunodeficient mice bearing orthotopically implanted human IL-13Rα2 expressing NCI-H1299 non-small cell lung cancer cells were injected intravenously with a single dose of LV vector pseudotyped with the TPMV H-IL-13 glycoprotein. Vector biodistribution was monitored using bioluminescence imaging of firefly luciferase transgene expression, revealing specific transduction of tumor tissue. A quantitative droplet digital PCR (ddPCR) analysis of lung tissue samples revealed a >15-fold increase in the tumor transduction in mice treated with LV vectors displaying IL-13 relative to those without IL-13. Our results show that TPMV envelope glycoproteins can be equipped with ligands to develop targeted LV vectors for in vivo applications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In vivo targeting of lentiviral vectors pseudotyped with the Tupaia paramyxovirus H glycoprotein bearing a cell-specific ligand

Argaw

Marino

Timmons

et al. 2021

Molecular Therapy - Methods & Clinical Development

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show abstract

“… 53 New generations of lentivirus vectors are derived from nonhuman lentiviruses and are theoretically more acceptable because their parental viruses are not infectious to humans. 54 Distinguishing characteristics of lentivirus vectors include: (1) capability of transducing both dividing and nondividing cells, (2) capability to enable long‐term gene expression, and (3) reduced risk of genotoxicity and insertional mutagenesis as compared to retrovirus vectors. The main disadvantage of lentivirus vectors is their limited genetic cargo capability.…”

Section: Clinically Relevant Viral Vectorsmentioning

confidence: 99%

Viral vector‐based gene therapies in the clinic

Zhao

Anselmo

Mitragotri

2021

Bioengineering & Transla Med

157

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Gene therapies are currently one of the most investigated therapeutic modalities in both the preclinical and clinical settings and have shown promise in treating a diverse spectrum of diseases. Gene therapies aim at introducing a gene material in target cells and represent a promising approach to cure diseases that were thought to be incurable by conventional modalities. In many cases, a gene therapy requires a vector to deliver gene therapeutics into target cells; viral vectors are among the most widely studied vectors owing to their distinguished advantages such as outstanding transduction efficiency. With decades of development, viral vector‐based gene therapies have achieved promising clinical outcomes with many products approved for treating a range of diseases including cancer, infectious diseases and monogenic diseases. In addition, a number of active clinical trials are underway to further expand their therapeutic potential. In this review, we highlight the diversity of viral vectors, review approved products, and discuss the current clinical landscape of in vivo viral vector‐based gene therapies. We have reviewed 13 approved products and their clinical applications. We have also analyzed more than 200 active trials based on various viral vectors and discussed their respective therapeutic applications. Moreover, we provide a critical analysis of the major translational challenges for in vivo viral vector‐based gene therapies and discuss possible strategies to address the same.

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“…LV vectors are also applied directly in vivo for therapeutic purposes. A non-primate LV vector system based on equine infectious anemia virus (EIAV) has been investigated clinically to treat ocular disorders [ 8 ]. In another in vivo application, an HIV-1-based, integration-deficient LV vector expressing the NY-ESO-1 cancer testis antigen targeted to dendritic cells was used to promote an immune response against NY-ESO-1-expressing tumors [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Tagging and Capturing of Lentiviral Vectors Using Short RNAs

Panigaj

Marino

Reiser

2021

IJMS

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Lentiviral (LV) vectors have emerged as powerful tools for transgene delivery ex vivo but in vivo gene therapy applications involving LV vectors have faced a number of challenges, including the low efficiency of transgene delivery, a lack of tissue specificity, immunogenicity to both the product encoded by the transgene and the vector, and the inactivation of the vector by the human complement cascade. To mitigate these issues, several engineering approaches, involving the covalent modification of vector particles or the incorporation of specific protein domains into the vector’s envelope, have been tested. Short synthetic oligonucleotides, including aptamers bound to the surface of LV vectors, may provide a novel means with which to retarget LV vectors to specific cells and to shield these vectors from neutralization by sera. The purpose of this study was to develop strategies to tether nucleic acid sequences, including short RNA sequences, to LV vector particles in a specific and tight fashion. To bind short RNA sequences to LV vector particles, a bacteriophage lambda N protein-derived RNA binding domain (λN), fused to the measles virus hemagglutinin protein, was used. The λN protein bound RNA sequences bearing a boxB RNA hairpin. To test this approach, we used an RNA aptamer specific to the human epidermal growth factor receptor (EGFR), which was bound to LV vector particles via an RNA scaffold containing a boxB RNA motif. The results obtained confirmed that the EGFR-specific RNA aptamer bound to cells expressing EGFR and that the boxB containing the RNA scaffold was bound specifically to the λN RNA binding domain attached to the vector. These results show that LV vectors can be equipped with nucleic acid sequences to develop improved LV vectors for in vivo applications.

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Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders

Cited by 26 publications

References 150 publications

In vivo targeting of lentiviral vectors pseudotyped with the Tupaia paramyxovirus H glycoprotein bearing a cell-specific ligand

In vivo targeting of lentiviral vectors pseudotyped with the Tupaia paramyxovirus H glycoprotein bearing a cell-specific ligand

Viral vector‐based gene therapies in the clinic

Tagging and Capturing of Lentiviral Vectors Using Short RNAs

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