The Old and the New: Prospects for Non-Integrating Lentiviral Vector Technology

Apolonia, Luis

doi:10.3390/v12101103

Cited by 38 publications

(15 citation statements)

References 112 publications

(126 reference statements)

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“…These LVs form nucleosomes that lead to chromatic silencing associated with histone modification in this chromatin structure. 90 With a higher capacity for transgene and elimination of potential mutagenesis associated with integration, nonintegrated LVs have a potential advantage over AAV vectors. Additionally, a portion of the methodologies focuses on (1) increasing transgene expression, (2) constructing fused genes, and (3) adding tags to transgene protein in the expression cassette and to allow the transgene to deliver to the target tissue efficiently.…”

Section: Discussionmentioning

confidence: 99%

Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Rintz

Higuchi

Kobayashi

et al. 2022

Molecular Therapy - Methods & Clinical Development

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More than 50 lysosomal storage diseases (LSDs) are associated with lysosomal dysfunctions with the frequency of 1:5,000 live births. As a result of missing enzyme activity, the lysosome dysfunction accumulates undegraded or partially degraded molecules, affecting the entire body. Most of them are life-threatening diseases where patients could die within the first or second decade of life. Approximately 20 LSDs have the approved treatments, which do not provide the cure for the disorder. Therefore, the delivery of missing genes through gene therapy is a promising approach for LSDs. Over the years, ex vivo lentiviral-mediated gene therapy for LSDs has been approached using different strategies. Several clinical trials for LSDs are under investigation. Ex vivo lentiviral-mediated gene therapy needs optimization in dose, time of delivery, and promoter-driven expression. Choosing suitable promoters seems to be one of the important factors for the effective expression of the dysfunctional enzyme. This review summarizes the research on therapy for LSDs that has used different lentiviral vectors, emphasizing gene promoters.

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Section: Discussionmentioning

confidence: 99%

Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Rintz

Higuchi

Kobayashi

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…For this reason, it appears that MLV-based vectors may not be clinically relevant without significant additional modification. Nonintegrating lentiviral vectors with enzymatic mutations of integrase are in development but have not yet entered clinical use (reviewed in (Luis, 2020)).…”

Section: Remaining Questions and Conclusionmentioning

confidence: 99%

Strategies for Targeting Retroviral Integration for Safer Gene Therapy: Advances and Challenges

Yoder

Rabe

Fishel

et al. 2021

Front. Mol. Biosci.

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Retroviruses are obligate intracellular parasites that must integrate a copy of the viral genome into the host DNA. The integration reaction is performed by the viral enzyme integrase in complex with the two ends of the viral cDNA genome and yields an integrated provirus. Retroviral vector particles are attractive gene therapy delivery tools due to their stable integration. However, some retroviral integration events may dysregulate host oncogenes leading to cancer in gene therapy patients. Multiple strategies to target retroviral integration, particularly to genetic safe harbors, have been tested with limited success. Attempts to target integration may be limited by the multimerization of integrase or the presence of host co-factors for integration. Several retroviral integration complexes have evolved a mechanism of tethering to chromatin via a host protein. Integration host co-factors bind chromatin, anchoring the complex and allowing integration. The tethering factor allows for both close proximity to the target DNA and specificity of targeting. Each retrovirus appears to have distinct preferences for DNA sequence and chromatin features at the integration site. Tethering factors determine the preference for chromatin features, but do not affect the subtle sequence preference at the integration site. The sequence preference is likely intrinsic to the integrase protein. New developments may uncouple the requirement for a tethering factor and increase the ability to redirect retroviral integration.

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“…Each modification leads to safer and more efficient generation. In the most recent gene therapy studies, third generation LVs are used [86][87][88][89].…”

Section: Lentiviral Vectorsmentioning

confidence: 99%

Gene Therapy for Neuronopathic Mucopolysaccharidoses: State of the Art

Castro

Toro

Giugliani

et al. 2021

IJMS

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The need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed.

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The Old and the New: Prospects for Non-Integrating Lentiviral Vector Technology

Cited by 38 publications

References 112 publications

Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Strategies for Targeting Retroviral Integration for Safer Gene Therapy: Advances and Challenges

Gene Therapy for Neuronopathic Mucopolysaccharidoses: State of the Art

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