Gene therapy comes of age

Dunbar, Cynthia E.; High, Katherine A.; Joung, Julia; Kohn, Donald B.; Ozawa, Keiya; Sadelain, Michel

doi:10.1126/science.aan4672

Cited by 1,108 publications

(835 citation statements)

References 151 publications

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“…The clinical trials showing positive efficacy and phenotypic results, combined with the advent of in-vivo gene therapy products (though mainly based on rAAV) being approved by regulatory authorities underscore this [2]. Inhibitory antibody responses to viral vectors remain a challenge, making effective repeat administration to achieve long-term transgene expression elusive.…”

Section: Resultsmentioning

confidence: 99%

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Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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Section: Resultsmentioning

confidence: 99%

“…Significant progress has been made, however, in genome editing where the mutation is corrected directly in the patient’s genome. Despite early setbacks [1], gene therapy has made important progress over the last decade [2]. For in-vivo application, the delivered nucleic acid is injected directly into the patient.…”

Section: Introductionmentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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“…[89] Therefore, the modification of a disease pathway is generally achieved by small molecules or peptides that modulate PPIs and selectively interfere with the downstream signaling cascades. However, correction of mutations using gene therapy is currently very limited and not yet available for PDZ domain proteins.…”

Section: Pharmacological Targeting Of Pdz Domainsmentioning

confidence: 99%

PDZ Domains as Drug Targets

Christensen

Čalyševa

Fernandes

et al. 2019

Advanced Therapeutics

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Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ domains play a role in several cellular functions, from cell-cell communication and polarization, to regulation of protein transport and protein metabolism. PDZ domain proteins are also crucial in the formation and stability of protein complexes, establishing an important bridge between extracellular stimuli detected by transmembrane receptors and intracellular responses. PDZ domains have been suggested as promising drug targets in several diseases, ranging from neurological and oncological disorders to viral infections. In this review, the authors describe structural and genetic aspects of PDZ-containing proteins and discuss the current status of the development of small-molecule and peptide modulators of PDZ domains. An overview of potential new therapeutic interventions in PDZ-mediated protein networks is also provided.

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“…Yet the first gene editing drug strategies were approved this year for producing CAR-T cells 113,114 and for treating a congenital cause of blindness (Luxturna) 115 using an engineered adeno-associated virus. Experiences with non-RNA-based gene editing tools, such as zinc-finger nucleases, and with siRNA drug delivery will facilitate development of CRISPR-Cas-based drugs 112,116 .…”

Section: Crispr-cas Gene Editingmentioning

confidence: 99%

Tapping the RNA world for therapeutics

Lieberman

2018

Nat Struct Mol Biol

163

127

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A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

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Gene therapy comes of age

Cited by 1,108 publications

References 151 publications

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

PDZ Domains as Drug Targets

Tapping the RNA world for therapeutics

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