Efficient Clinical Scale Gene Modification via Zinc Finger Nuclease–Targeted Disruption of the HIV Co-receptor CCR5

Maier, Dawn; Brennan, Andrea; Jiang, Shuguang; Binder-Scholl, Gwendolyn; Lee, Gary; Plesa, Gabriela; Zheng, Zhaohui; Cotte, Julio; Carpenito, Carmine; Wood, Travis; Spratt, S. Kaye; Ando, Dale; Gregory, Philip D.; Holmes, Michael C.; Perez, Elena E.; Riley, James L.; Carroll, Richard G.; June, Carl H.; Levine, Bruce L.

doi:10.1089/hum.2012.172

Cited by 109 publications

(74 citation statements)

References 78 publications

(115 reference statements)

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“…Thus, HIV itself supports the outgrowth of genemodified resistant cells. This was demonstrated in vitro with adenoviral delivery of CCR5 ZFNs, which conferred resistance of human primary CD4 + T cells and HSPCs to HIV infection [71][72][73][74].…”

Section: Locking Out Hiv: Gene Therapy Strategies That Target Hiv Entrymentioning

confidence: 99%

Personalized gene therapy locks out HIV, paving the way to control virus without antiretroviral drugs

Levine

Leskowitz

Davis

2015

Expert Opinion on Biological Therapy

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In concept, a single infusion of genetically modified cells could potentially reduce the need for lifelong medication by providing long-term control over the virus (functional immunity). While the dream of completely eliminating viral reservoirs (sterilizing immunity) is appealing, this presents a significant additional hurdle and may not be necessary to improve long-term health. A single infusion, or a small number of infusions, of engineered cells may be shown in confirmatory clinical trials to produce a meaningful biologic effect. These techniques have implications for targeted gene therapy in HIV and other diseases.

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Section: Locking Out Hiv: Gene Therapy Strategies That Target Hiv Entrymentioning

confidence: 99%

Personalized gene therapy locks out HIV, paving the way to control virus without antiretroviral drugs

Levine

Leskowitz

Davis

2015

Expert Opinion on Biological Therapy

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“…38 Subsequently, Ad5/F35 delivery of this ZFN pair to CD3/CD28-stimulated CD4 1 T cells was adapted for clinical scale, allowing the production of .10 10 CCR5-edited cells and paving the way for phase 1 clinical studies. 40 The first-in-human genome editing trial to treat HIV (#NCT00842634) was initiated in 2009, primarily to evaluate the safety of modifying autologous CD4…”

Section: T Cellsmentioning

confidence: 99%

The clinical applications of genome editing in HIV

Wang

Cannon

2016

Blood

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HIV/AIDS has long been at the forefront of the development of gene- and cell-based therapies. Although conventional gene therapy approaches typically involve the addition of anti-HIV genes to cells using semirandomly integrating viral vectors, newer genome editing technologies based on engineered nucleases are now allowing more precise genetic manipulations. The possible outcomes of genome editing include gene disruption, which has been most notably applied to the CCR5 coreceptor gene, or the introduction of small mutations or larger whole gene cassette insertions at a targeted locus. Disruption of CCR5 using zinc finger nucleases was the first-in-human application of genome editing and remains the most clinically advanced platform, with 7 completed or ongoing clinical trials in T cells and hematopoietic stem/progenitor cells (HSPCs). Here we review the laboratory and clinical findings of CCR5 editing in T cells and HSPCs for HIV therapy and summarize other promising genome editing approaches for future clinical development. In particular, recent advances in the delivery of genome editing reagents and the demonstration of highly efficient homology-directed editing in both T cells and HSPCs are expected to spur the development of even more sophisticated applications of this technology for HIV therapy.

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“…Clinical scale ZFN-directed disruption of CCR5 in T cells has been achieved using a chimeric Ad5/F35 adenovirus and anti-CD3/anti-CD28 costimulation of T cells, generating more than 10 billion CCR5 gene-edited CD4? T cells [95,96], which led to FDA-approved clinical trials (www. clinicaltrials.gov identifier number NCT00842634, NCT01044654 and NCT01252641).…”

Section: Zfns In Therapeutic Applicationsmentioning

confidence: 99%

Recent developments and clinical studies utilizing engineered zinc finger nuclease technology

Kim

Ramakrishna

2015

Cell. Mol. Life Sci.

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Efficient methods for creating targeted genetic modifications have long been sought for the investigation of gene function and the development of therapeutic modalities for various diseases, including genetic disorders. Although such modifications are possible using homologous recombination, the efficiency is extremely low. Zinc finger nucleases (ZFNs) are custom-designed artificial nucleases that make double-strand breaks at specific sequences, enabling efficient targeted genetic modifications such as corrections, additions, gene knockouts and structural variations. ZFNs are composed of two domains: (i) a DNA-binding domain comprised of zinc finger modules and (ii) the FokI nuclease domain that cleaves the DNA strand. Over 17 years after ZFNs were initially developed, a number of improvements have been made. Here, we will review the developments and future perspectives of ZFN technology. For example, ZFN activity and specificity have been significantly enhanced by modifying the DNA-binding domain and FokI cleavage domain. Advances in culture methods, such as the application of a cold shock and the use of small molecules that affect ZFN stability, have also increased ZFN activity. Furthermore, ZFN-induced mutant cells can be enriched using episomal surrogate reporters. Additionally, we discuss several ongoing clinical studies that are based on ZFN-mediated genome editing in humans. These breakthroughs have substantially facilitated the use of ZFNs in research, medicine and biotechnology.

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Efficient Clinical Scale Gene Modification via Zinc Finger Nuclease–Targeted Disruption of the HIV Co-receptor CCR5

Cited by 109 publications

References 78 publications

Personalized gene therapy locks out HIV, paving the way to control virus without antiretroviral drugs

Personalized gene therapy locks out HIV, paving the way to control virus without antiretroviral drugs

The clinical applications of genome editing in HIV

Recent developments and clinical studies utilizing engineered zinc finger nuclease technology

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