Engineering Gene Therapy: Advances and Barriers

Shahryari, Ali; Burtscher, Ingo; Nazari, Zahra; Lickert, Heiko

doi:10.1002/adtp.202100040

Cited by 35 publications

(31 citation statements)

References 422 publications

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“…However, despite significant progress in pre-clinical and clinical studies, not a single anti-cancer OGT agent has been approved for clinical use [5][6][7]. The major problems in OGT development include inefficient intracellular delivery, lower efficiency, and high cost [2,3]. This review analyzes yet another important issue, the specificity of Ivyspring International Publisher OGT agents.…”

Section: Oligonucleotide-based Gene Therapy (Ogt)mentioning

confidence: 99%

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Specificity of oligonucleotide gene therapy (OGT) agents

Nedorezova¹,

Dubovichenko²,

Belyaeva³

et al. 2022

Theranostics

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Oligonucleotide gene therapy (OGT) agents (e. g. antisense, deoxyribozymes, siRNA and CRISPR/Cas) are promising therapeutic tools. Despite extensive efforts, only few OGT drugs have been approved for clinical use. Besides the problem of efficient delivery to targeted cells, hybridization specificity is a potential limitation of OGT agents. To ensure tight binding, a typical OGT agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence. However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma. Here, we assess the scale of this problem by analyzing OGT hybridization-dependent off-target effects (HD OTE) in vitro , in animal models and clinical studies. All OGT agents except deoxyribozymes exhibit HD OTE in vitro , with most thorough evidence of poor specificity reported for siRNA and CRISPR/Cas9. Notably, siRNA suppress non-targeted genes due to (1) the partial complementarity to mRNA 3'-untranslated regions (3'-UTR), and (2) the antisense activity of the sense strand. CRISPR/Cas9 system can cause hundreds of non-intended dsDNA breaks due to low specificity of the guide RNA, which can limit therapeutic applications of CRISPR/Cas9 by ex-vivo formats. Contribution of this effects to the observed in vivo toxicity of OGT agents is unclear and requires further investigation. Locked or peptide nucleic acids improve OGT nuclease resistance but not specificity. Approaches that use RNA marker dependent (conditional) activation of OGT agents may improve specificity but require additional validation in cell culture and in vivo .

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Section: Oligonucleotide-based Gene Therapy (Ogt)mentioning

confidence: 99%

“…antibodies) 1 . OGT has been under development for over 40 years 2 . It aims at suppressing genes either responsible for the development of human diseases or interfering with conventional treatment (e.g.…”

Section: Introductionmentioning

confidence: 99%

Specificity of oligonucleotide gene therapy (OGT) agents

Nedorezova¹,

Dubovichenko²,

Belyaeva³

et al. 2022

Theranostics

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“…Avoiding unintended changes in important genomic regions remains a major consideration during genome engineering. A large amount of effort has been spent to establish complicated experiment systems to identify and prevent these potential deleterious effects [36][37][38]. However, since the functional consequences of genomic alternation may only be detected in a specific cell type during a specific development stage and/or under specific conditions, it is challenging to include all these factors in the experimental design.…”

Section: Discussionmentioning

confidence: 99%

Genomics and epigenetics guided identification of tissue-specific genomic safe harbors

Shrestha

Bag

et al. 2022

Genome Biol

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Background Genomic safe harbors are regions of the genome that can maintain transgene expression without disrupting the function of host cells. Genomic safe harbors play an increasingly important role in improving the efficiency and safety of genome engineering. However, limited safe harbors have been identified. Results Here, we develop a framework to facilitate searches for genomic safe harbors by integrating information from polymorphic mobile element insertions that naturally occur in human populations, epigenomic signatures, and 3D chromatin organization. By applying our framework to polymorphic mobile element insertions identified in the 1000 Genomes project and the Genotype-Tissue Expression (GTEx) project, we identify 19 candidate safe harbors in blood cells and 5 in brain cells. For three candidate sites in blood, we demonstrate the stable expression of transgene without disrupting nearby genes in host erythroid cells. We also develop a computer program, Genomics and Epigenetic Guided Safe Harbor mapper (GEG-SH mapper), for knowledge-based tissue-specific genomic safe harbor selection. Conclusions Our study provides a new knowledge-based framework to identify tissue-specific genomic safe harbors. In combination with the fast-growing genome engineering technologies, our approach has the potential to improve the overall safety and efficiency of gene and cell-based therapy in the near future.

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“…The first gene therapy product was actually a recombinant human p53 adenovirus for the treatment of head and neck cancer that was approved by the China Food and Drug Administration (CFDA) in 2003 and hit the market in 2004 [137]. In 2017, the first gene therapies were FDA approved and as of now, there are ~20 FDA approved gene therapies, with thousands in clinical trials [138][139][140]. With this exploding technology, there is a significant amount of ongoing research dedicated to developing new and improved gene therapies.…”

Section: Gene Therapymentioning

confidence: 99%

Virus Like Particles: A Self-Assembled Toolbox for Cancer Therapy

Shahrivarkevishahia

Hagge

Brohlin

et al. 2022

Preprint

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Nanoparticle-based therapeutics have been applied in a broad range of clinical and pre-clinical applications from diagnosis to treatment for cancer. A wide range of synthetic and naturally occurring materials such as polymers, metal oxides, silicate, liposomes, and carbon nanotubes have been developed to overcome key barriers in small molecule therapeutics including intracellular trafficking, cell/tissue targeting, poor biodistribution, and low efficiency. Virus like particles (VLPs)—engineered and non-infectious self-assembling systems based on viral nanostructures—are new approach toward overcoming these limitations, as they are a protein-based nanomaterial that closely mimics the highly symmetrical and polyvalent conformation of viruses while lacking the viral genomes. Their innate biocompatibility, biodegradability, monodispersity, mild immunogenicity, and safety combined with the capacity to chemically modify the interior and exterior surfaces of these systems offer scientists a highly customizable tool to design and engineer multi-component therapeutic agents. In this review, we discuss how these systems have been used in a wide array of cancer treatments including phototherapy, immunotherapy, gene therapy, and chemotherapy.

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Engineering Gene Therapy: Advances and Barriers

Cited by 35 publications

References 422 publications

Specificity of oligonucleotide gene therapy (OGT) agents

Specificity of oligonucleotide gene therapy (OGT) agents

Genomics and epigenetics guided identification of tissue-specific genomic safe harbors

Virus Like Particles: A Self-Assembled Toolbox for Cancer Therapy

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