Viral vectors for gene therapy: Current state and clinical perspectives

Lukashev, Alexander N.; Zamyatnin, Andrey A.

doi:10.1134/s0006297916070063

Cited by 120 publications

(80 citation statements)

References 42 publications

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“…Viral vectors are designed to deliver a payload to the target cells by utilizing the viral infection pathway, while most of the non-essential viral genome is removed from the vector. Integration-deficient lentiviruses, adenoviruses, and adeno-associated viruses are the most popular viral vectors for gene therapy due to their nonintegrating nature, eliminating the risks of mutagenesis and tumorigenicity associated with gene insertion (Yin et al 2017;Lukashev and Zamyatnin 2016;Lundstrom 2018). Among them, adeno-associated viruses are particularly attractive for their low immunogenicity and broad ability to target specific tissues, including liver, brain, skeletal, kidney, retina, lung, and vascular tissue (Mingozzi and High 2011).…”

Section: Diseases Benefitting From In Vivo Gene Editingmentioning

confidence: 99%

Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications

et al. 2019

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Progress in targeted gene editing by programmable endonucleases has paved the way for their use in gene therapy. Particularly, Cas9 is an endonuclease with high activity and flexibility, rendering it an attractive option for therapeutic applications in clinical settings. Many disease-causing mutations could potentially be corrected by this versatile new technology. In addition, recently developed switchable Cas9 variants, whose activity can be controlled by an external stimulus, provide an extra level of spatiotemporal control on gene editing and are particularly desirable for certain applications. Here, we discuss the considerations and difficulties for implementing Cas9 to in vivo gene therapy. We put particular emphasis on how switchable Cas9 variants may resolve some of these barriers and advance gene therapy in the clinical setting.

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Section: Diseases Benefitting From In Vivo Gene Editingmentioning

confidence: 99%

Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications

et al. 2019

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“…However, it has its drawbacks. For example, the organism may develop an immune response, resulting in the loss in delivery effectiveness with repeated injections (Lukashev, Zamyatnin, 2016). Another problem is the stereotaxic method of delivery of the virus.…”

Section: Viral Vectorsmentioning

confidence: 99%

Genetic approaches to the investigation of serotonergic neuron functions in animals

2019

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The serotonergic system is one of the most important neurotransmitter systems that take part in the regulation of vital CNS functions. The understanding of its mechanisms will help scientists create new therapeutic approaches to the treatment of mental and neurodegenerative diseases and find out how this neurotransmitter system interacts with other parts of the brain and regulates their activity. Since the serotonergic system anatomy and functionality are heterogeneous and complex, the best tools for studying them are based on manipulation of individual types of neurons without affecting neurons of other neurotransmitter systems. The selective cell control is possible due to the genetic determinism of their functions. Proteins that determine the uniqueness of the cell type are expressed under the regulation of cell-specific promoters. By using promoters that are specific for genes of the serotonin system, one can control the expression of a gene of interest in serotonergic neurons. Here we review approaches based on such promoters. The genetic models to be discussed in the article have already shed the light on the role of the serotonergic system in modulating behavior and processing sensory information. In particular, genetic knockouts of serotonin genes sert, pet1, and tph2 promoted the determination of their contribution to the development and functioning of the brain. In addition, the review describes inducible models that allow gene expression to be controlled at various developmental stages. Finally, the application of these genetic approaches in optogenetics and chemogenetics provided a new resource for studying the functions, discharge activity, and signal transduction of serotonergic neurons. Nevertheless, the advantages and limitations of the discussed genetic approaches should be taken into consideration in the course of creating models of pathological conditions and developing pharmacological treatments for their correction.

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“…Recent success in the treatment of LCA, as reviewed above, has brought about the evaluation of AAV vector-mediated gene replacement in choroideremia. The cloning capacity of AAV vectors is approximately 4.5-5.0 kb, which is greater than the approximately 1.9 kb coding sequence of REP-1, making it an excellent vector for delivery (48)(49)(50). The replacement of the REP-1 gene was evaluated in a choroideremia murine model, in which mice were designed to have an REP-1 deficiency.…”

Section: Gene Therapies For Choroideremiamentioning

confidence: 99%

Gene therapy for inherited retinal and optic nerve degenerations

Moore

Morral

Ciulla

et al. 2017

Expert Opinion on Biological Therapy

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The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

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Viral vectors for gene therapy: Current state and clinical perspectives

Cited by 120 publications

References 42 publications

Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications

Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications

Genetic approaches to the investigation of serotonergic neuron functions in animals

Gene therapy for inherited retinal and optic nerve degenerations

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