Clinical Applications of Genome Editing to HIV Cure

Wang, Cathy X.; Cannon, Paula M.

doi:10.1089/apc.2016.0233

Cited by 11 publications

(9 citation statements)

References 62 publications

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“…Presumably, a similar approach can be used to commercialize products resulted from GET. The potential of such products is currently studied in clinical trials: from treating HIV infection and blood diseases by modifying hematopoietic stem cells [3,21] to treating B-cell lymphomas with CAR-T-lymphocytes [22] and treating bullous epidermolysis by genetically modified epithelial cells [23].…”

Section: Rationale and Basic Approaches To Ethical And Legal Regulatimentioning

confidence: 99%

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Ethical and Legal Aspects of Using Genome Editing Technologies in Medicine (Review)

Karagyaur¹,

Efimenko²,

Макаревич³

et al. 2019

Sovrem Tehnol Med

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According to many experts, the turning point in the development of genome editing technologies (GET) was 2012, when Feng Zhang and Jennifer Doudna independently proposed the adaptive bacterial immunity system CRISPR/Cas9 for editing the genome of living cells of eukaryotic organisms. Since then, the range of applications of CRISPR/Cas9 technology and related GET has continued to grow like an avalanche. Thus, new genetically modified microorganisms, plants, and animals have been created, the experimental studies on the genetic foundations of life have greatly expanded, and revolutionary approaches to therapy and prevention of incurable diseases have been developed. However, the indisputable advantages of GET are associated with high risks (real and potential) to the environment, human health, and society as a whole. Significant progress in the genome editing in eukaryotes has led to a rapid appearance of humans with an "improved" genome, despite the openly expressed opposition of leading scientists working in this field. Among them, David Baltimore, Paul Berg, Jennifer Doudna, George Church, and Martin Jinek are calling for a global suspension of work with human embryos until the technical, legal and ethical standards in this area are developed. There is an urgent need for the development of an unambiguous public position and improvement of the regulatory framework for the GET, including that in the Russian Federation; the present review attempts to address the urgent issue of GET-related regulations. We discuss various approaches to regulating the use of GET in medicine. We review legal acts and ethical recommendations around the world concerning the GET-mediated modification of the plant and animal genetic material for the purpose of creating medical products and drugs. We also address the sensitive issue of editing the genome of human cells (somatic or germ). Special attention is paid to the relevant legal and ethical standards exiting in the Russian Federation. The presented data allow for a better understanding of the current situation and the areas of further research into GET, where the development and implementation of regulatory standards are especially urgent.

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Section: Rationale and Basic Approaches To Ethical And Legal Regulatimentioning

confidence: 99%

“…These novel techniques make it possible to find solutions to urgent medical problems, such as elucidating the molecular mechanisms of diseases, diagnosing and treating incurable diseases (HIV, oncological and orphan diseases), as well as controlling the spread of vector-borne infections (malaria, sleeping sickness, fever, etc.) [3,4].…”

Section: Introductionmentioning

confidence: 99%

Ethical and Legal Aspects of Using Genome Editing Technologies in Medicine (Review)

Karagyaur¹,

Efimenko²,

Макаревич³

et al. 2019

Sovrem Tehnol Med

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“…Gene therapy may represent a valuable alternative approach for AIDS treatment. One approach with ZFN-CCR5-modified autologous T cells of HIV-infected subjects is evaluated in an ongoing Phase 2 trial (SB-728) [ 35 ]. Although HIV-1 strains use CCR5 as a major coreceptor when establishing initial infections, CXCR4 is also a coreceptor for CXCR4-tropic HIV-1 infection in vivo [ 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection

et al. 2017

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Background:The CRISPR/Cas9 system has been widely used for genome editing in mammalian cells. CXCR4 is a co-receptor for human immunodeficiency virus type 1 (HIV-1) entry, and loss of CXCR4 function can protect cells from CXCR4 (X4)-tropic HIV-1 infection, making CXCR4 an important target for HIV-1 gene therapy. However, the large size of the CRISPR/SpCas9 system presents an obstacle to its efficient delivery into primary CD4 + T cells. Recently, a small Staphylococcus aureus Cas9 (SaCas9) has been developed as a genome editing tool can address this question. Therefore, it provides a promising strategy for HIV-1 gene therapy if it is used to target CXCR4. Results:Here, we employed a short version of Cas9 from Staphylococcus aureus (SaCas9) for targeting CXCR4. We demonstrated that transduction of lenti-virus expressing SaCas9 and selected single-guided RNAs of CXCR4 in human CD4 + T cell lines efficiently induced the editing of the CXCR4 gene, making these cell lines resistant to X4-tropic HIV-1 infection. Moreover, we efficiently transduced primary human CD4 + T cells using adeno-associated virus-delivered CRISPR/SaCas9 and disrupted CXCR4 expression. We also showed that CXCR4-edited primary CD4 + T cells proliferated normally and were resistant to HIV-1 infection. Conclusions:Our study provides a basis for possible application of CXCR4-targeted genome editing by CRISPR/ SaCas9 in HIV-1 gene therapy.

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“…Gene editing strategies utilizing AAV serotype encoding ZFN has shown the most promising results amongst other editing nuclease platforms. It was demonstrated to be successful in treating hepatic dysfunctions in hemophilia B and hereditary tyrosinemia mouse models and phase I clinical trials are underway for the treatment of human HIV and Hunter’s syndrome [ 26 , 36 , 99 ]. Current gene manipulation techniques differ from one another in several ways (target site recognition sequence, protein size, and difficulty of engineering) and have their respective pros and cons (summarized in Table 2 ).…”

Section: Advantages and Limitations Of In Vivo Gene Editingmentioning

confidence: 99%

In Vivo Genome Editing as a Therapeutic Approach

Loh

Chan

et al. 2018

IJMS

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Genome editing has been well established as a genome engineering tool that enables researchers to establish causal linkages between genetic mutation and biological phenotypes, providing further understanding of the genetic manifestation of many debilitating diseases. More recently, the paradigm of genome editing technologies has evolved to include the correction of mutations that cause diseases via the use of nucleases such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs), and more recently, Cas9 nuclease. With the aim of reversing disease phenotypes, which arise from somatic gene mutations, current research focuses on the clinical translatability of correcting human genetic diseases in vivo, to provide long-term therapeutic benefits and potentially circumvent the limitations of in vivo cell replacement therapy. In this review, in addition to providing an overview of the various genome editing techniques available, we have also summarized several in vivo genome engineering strategies that have successfully demonstrated disease correction via in vivo genome editing. The various benefits and challenges faced in applying in vivo genome editing in humans will also be discussed.

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Clinical Applications of Genome Editing to HIV Cure

Abstract: Despite significant advances in HIV drug treatment regimens, which grant near-normal life expectancies to infected individuals who have good virological control, HIV infection itself remains incurable.

Cited by 11 publications

References 62 publications

Ethical and Legal Aspects of Using Genome Editing Technologies in Medicine (Review)

Ethical and Legal Aspects of Using Genome Editing Technologies in Medicine (Review)

Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection

In Vivo Genome Editing as a Therapeutic Approach

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