Toward Responsible Human Genome Editing

Hynes, Richard O.; Coller, Barry S.; Porteus, Matthew H.

doi:10.1001/jama.2017.4548

Cited by 13 publications

(8 citation statements)

References 22 publications

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“…T he discovery of gene editing and programmable genomic control by clustered regularly interspaced short palindromic repeat (CRISPR) RNAs (crRNAs) and their CRISPR-associated (Cas) proteins [1][2][3][4][5] holds tremendous promise for future therapeutics and curing genetic diseases [6][7][8][9][10][11]. Despite their potential, CRISPR enzymes are not optimal for therapeutic applications [9,10,[12][13][14]. For example, they invariably suffer from unwanted ''off-target'' editing that can be difficult to predict, detect, or prevent [12,[15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Rationally Designed Anti-CRISPR Nucleic Acid Inhibitors of CRISPR-Cas9

Barkau

O'Reilly

Rohilla

et al. 2019

Nucleic Acid Therapeutics

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Clustered regularly interspaced short palindromic repeat (CRISPR) RNAs and their associated effector (Cas) enzymes are being developed into promising therapeutics to treat disease. However, CRISPR-Cas enzymes might produce unwanted gene editing or dangerous side effects. Drug-like molecules that can inactivate CRISPR-Cas enzymes could help facilitate safer therapeutic development. Based on the requirement of guide RNA and target DNA interaction by Cas enzymes, we rationally designed small nucleic acid-based inhibitors (SNuBs) of Streptococcus pyogenes (Sp) Cas9. Inhibitors were initially designed as 2¢-O-methyl-modified oligonucleotides that bound the CRISPR RNA guide sequence (anti-guide) or repeat sequence (anti-tracr), or DNA oligonucleotides that bound the protospacer adjacent motif (PAM)-interaction domain (anti-PAM) of SpCas9. Coupling anti-PAM and anti-tracr modules together was synergistic and resulted in high binding affinity and efficient inhibition of Cas9 DNA cleavage activity. Incorporating 2¢F-RNA and locked nucleic acid nucleotides into the anti-tracr module resulted in greater inhibition as well as dose-dependent suppression of gene editing in human cells. CRISPR SNuBs provide a platform for rational design of CRISPR-Cas enzyme inhibitors that should translate to other CRISPR effector enzymes and enable better control over CRISPR-based applications.

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Section: Introductionmentioning

confidence: 99%

Rationally Designed Anti-CRISPR Nucleic Acid Inhibitors of CRISPR-Cas9

Barkau

O'Reilly

Rohilla

et al. 2019

Nucleic Acid Therapeutics

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“…A new organization, Association for Responsible Research and Innovation in Genome Editing (ARRIGE), was established by a group of European scientists with a mission of valuing and making policy for the ethical use of genome editing. 145 , 146 Furthermore, Janasoff et al proposed to establish and develop an interdisciplinary, international global observatory for gene editing. 147 In 2018, a Chinese scientist declared that, with the help of CRISPR-Cas9 technology, the world's first genetically edited babies, who may be immune to HIV, had been created.…”

Section: Ethicsmentioning

confidence: 99%

Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics

Liu

Jiang

et al. 2021

Precision Clinical Medicine

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Clustered regularly interspaced short palindromic repeats-CRISPR associated systems (Cas) are efficient tools for targeting specific genes for laboratory research, agricultural engineering, biotechnology, and human disease treatment. Cas9, by far the most extensively used gene-editing nuclease, has shown great promise for the treatment of hereditary diseases, viral infection, cancers and so on. Recent reports have revealed that some other types of CRISPR-Cas systems may also have surprising potential to join the fray as gene-editing tools for various applications. Despite the fast progress in basic researches and clinical tests, some underlying problems present continuous, significant challenges, such as editing efficiency, relative difficulty in delivery, off-target effects, immunogenicity, etc. This article summarizes the applications of CRISPR-Cas from bench to bedside and highlights the current obstacles that may limit the usage of CRISPR-Cas systems as gene-editing tool-kits in precision medicine and offer some viewpoints that may help to tackle these challenges and facilitate technical development. CRISPR-Cas systems, as a powerful gene-editing approach, will offer great hopes in clinical treatments for many individuals with currently incurable diseases.

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“…The ability not only to detect disease but also to eradicate it altogether may well change the way in which reproduction is understood . Such a change raises a host of questions.…”

Section: Ethical Issues and Clinical Possibilitiesmentioning

confidence: 99%

Parenting in the Age of Preimplantation Gene Editing

Klipstein¹

2017

Hastings Center Report

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Medical science at its core aims to preserve health and eliminate disease, but a common theme in scientific discovery is the application of findings in ways that were not the primary intent. The development of diagnostic modalities to predict the health of resulting children has been a fundamental aim underpinning research into prenatal and preimplantation diagnostic modalities; however, the knowledge gained has in some cases been utilized for nonmedical purposes. As an example, amniocentesis developed to determine whether the pregnancy is chromosomally normal also provides information about the sex of the fetus, which normally does not affect health. The emerging gene‐editing technologies that could be used to repair mutated disease‐causing genes in an embryo will presumably also be able to be used to alter traits unrelated to disease. And yet, I will argue, the desire to preserve the mystery of reproduction remains a central value in humans’ quest to reproduce. This yearning to maintain the mysteries will likely temper the development of strategies to alter our genome and affect the genetic identities of our offspring. In my experience as an obstetrician and reproductive endocrinology and infertility subspecialist, people want to have, not the best possible baby, but rather their own baby.

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Toward Responsible Human Genome Editing

Cited by 13 publications

References 22 publications

Rationally Designed Anti-CRISPR Nucleic Acid Inhibitors of CRISPR-Cas9

Rationally Designed Anti-CRISPR Nucleic Acid Inhibitors of CRISPR-Cas9

Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics

Parenting in the Age of Preimplantation Gene Editing

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