CRISPR-Cas9: Timeline of key events

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Summit recommended the continuation of basic and clinical research of the applications gene editing in somatic cells, but stressed it would be 'irresponsible to proceed with any clinical use of germline editing' until the technology's safety and efficacy issues were better understood. 2015-12-01T00:00:00+0000The work laid a pathway for using CRISPR to correct genetic mutatiuons in affected tissues of sick patients. It was published in CE Nelson, CH Hakim, DG Ousterout, PI Thakore et al, 'In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy', Science, DOI: 10.1126/science.aad51432015-12-31T00:00:00+0000Kleinstiver, B P, Pattanayak, V, Prew, M S, Tsai, S Q, Nguyen, N T, Zheng, Z, Joung, K, 'High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off-target effects', Nature, doi:10.1038.2016-01-06T00:00:00+0000The UK Human Fertilisation and Embryology Authority (HEFA) gave the go ahead to a team at the Crick institute, led by Kathy Nikan, to edit human embyos to understand the genetic cause of miscarriage. It was the first time HEFA gave permission for the use of gene editing in human embryos. Nikan's team proposed to use embryos left over from patients' fertility treatment and donated by patients. The aim of the work was to introduce the Cas9 protein and guide RNA into human embryos at the one-cell stage to inactivate genes that could be important for early development and investigate their role. All the CRISP-targeted embryos would have their development stopped within seven days of fertilisation and analysed for any DNA changes. 2016-02-01T00:00:00+0000A.C. Komor, Y.B. Kim, M.S. Packer, J.A. Zuris, D.R. Liu, 'Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage', Nature, 533/7603 (2016), 420–24.2016-05-16T00:00:00+0000The trial was proposed by Carl June at University of Pennsylvannia to treat patients with multiple myeloma, melanoma and sarcoma. The study was approved by the US NIH Recombinant DNA Advisory Committee. It approved the use of CRISPR/Cas 9 to genetically modify immune cells to attack cancer in 18 patients. The trial was designed to test whether CRISPR is safe for use in humans. 2016-06-21T00:00:00+0000While granting permission the Academies urged caution. NAS and NAM, Human Genome Editing: Science, Ethics and Governance, February 20172017-02-24T00:00:00+0000J. S. Gootenberg, O.O. Abudayyeh, J. W. Lee, et al, 'Nucleic acid detection with CRISPR-Cas13a/C2c2', Science, 13 April 2017, eaam9321, DOI: 10.1126/science.aam9321 2017-04-13T00:00:00+0000The experiment was carried out by scientists at Sichuan University, Temple University and the University of Pittsburgh. It was published in C. Yin, et al, 'In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-Guide RNAs in Animal Models', Molecular Therapy, 25/5 (2017), 1168-86.2017-05-13T00:00:00+0000M. Hong, N. Marti-Gutierrez, S-W Park, et al, 'Correction of a pathogenic gene mutation in human embryos', Nature, doi:10.1038/nature233052017-08-02T00:00:00+0000UK scientists modified 41 embryos shortly after fertilisation. N.M.E. Fogarty et al, 'Genome editing reveals a role for OCT4 in human embryogenesis', Nature, doi:10.1038/nature240332017-09-20T00:00:00+0000P. Liang, et al, 'Correction of beta-thalassemia mutant by base editor in human embryos', Protein and Cell (2017), doi.org/10.1007/s13238-017-0475-6.2017-09-23T00:00:00+0000The method provided a means to fix genetic mutations without tampering with the genome. It was published in D.B.T. Cox, J.S. Gootenberg, O.O. Abudayyeh, B.Franklin, M.J. Kellner, et al, 'RNA editing with CRISPR-Cas13', Science (25 Oct 2017), eaaq0180, DOI: 10.1126/science.aaq01802017-10-25T00:00:00+0000N.M. Gaudelli, A. Komor, H. A. Rees, M. S. Packer, A. H. Badran, D. I. Bryson, D. R. Liu, 'Programmable base editing of A-T to G-C in genomic DNA without DNA cleavage', Nature (2017), doi:10.1038/nature24644. 2017-10-25T00:00:00+0000C T Charlesworth et al, 'Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans', bioRXiv (2018), https://doi.org/10.1101/2433452018-01-05T00:00:00+0000The phase 1/2 trial is designed to test the genome-editing technique in patients with transfusion-dependent beta-thalassemia, an inherited blood disorder. Sponsored by Vertex Pharmaceuticals and CRISPR Therapeutics the trial is being conducted at a single hospital in Regensburg Germany and will recruit 12 adults. It is testing CTX001, a gene-editing therapy that targets a region of DNA that acts like a brake on production of fetal haemoglobin, a type of haemoglobin that the body usually stops producing after the first months of life. Treatment involves taking blood from the patient and genetically altering them in the laboratory so that they when reintroduced into the patient are able to produce red blood cells that contain fetal haemoglobulin. 2018-08-27T00:00:00+0000He Jiankui, a genome-editing researcher at Southern University of Science and Technology of China, reported transplanting embryos into a woman that he had edited with CRISPR-Cas9 to disable a gene called CCR5, to disable the genetic pathway HIV uses to infect cells. More than 100 Chinese biomerical researchers condemned the experiment and called on Chinese authorities to investigate the case and introduce strict regulations. 2018-11-24T00:00:00+0000The efficacy of the technique was tested in mice genetically modified to have only one working copy of genes known to regulate satiety (Sim1) and hunger (MC4R). CRISPRa was shown to increase the expression of the genes in the mice. Mice that had missing one copy of the Sim1 gene that received CRISPRa injections were found to maintain a healthy body weight like normal mice, whereas those that did not get the injections could not stop eating and developed severe obesity on a normal diet. The research was published in N Matharu et al, 'CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency', Science 362/6420 (2018) eaau0629, DOI: 10.1126/science.aau06292018-12-14T00:00:00+0000Scientists found that it was possible to stop tumour growth in both tissue culture and in a mouse by disabling the tumour gene, NRF2, that helps the tumours develop resistance to drugs. They achieved this by using the CRISPR-Cas9 gene editing system. The work was led by Eric Kmiec at the Gene Editing Institute of the Helen F Graham Cancer Center and Research Institute, USA. It was published in P Bialk, Y Wang, K Banas, E B Kmiec, ' Functional Gene Knockout of NRF2 Increases Chemosensitivity of Human Lung Cancer A549 Cells In Vitro and in a Xenograft Mouse Model', Molecular Therapy Oncolytics', 11 (Dec 21 2018), DOI:https://doi.org/10.1016/j.omto.2018.10.0022018-12-21T00:00:00+0000A team of scientists managed to engineer mice to express Cas9 and a DNA sequence needed for the gene drive, called a cassette, which encoded a guide RNA that targets a sequence in the TYR gene which affects the mouse coat colour. This provided a means of tracking the frequency of the genetic modification over several generations of mice. The work was published in HA Grunwald et al. 'Super-Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline', Nature, January 23, 2019.2019-01-23T00:00:00+0000
Date Event People Places Sciences
1 Dec 2015International Summit on Human Gene Editing met to discuss the scientific, medical, ethical, and governance issues associated with recent advances in human gene-editing researchBaltimore, Doudna, Church, ZhangUS National Academies of Science, Engineering and Medicine, US National Academy of Medicine, Chinese Academy of Sciences, Royal SocietyCRISPR-Cas9, Gene editing
31 Dec 2015Gene editiing tool, CRISPR, successfully used to improve muscle function in mouse model of Duchenne muscular dystrophyNelson, Gersbach, Hakim, Ousterout, ThakoreDuke University, University of Missouri, University of North Carolina, Massachusetts Institute of Technology, Harvard UniversityCRISPR-Cas9, Gene editing, Gene therapy
6 Jan 2016US scientists published improved version of CRISPR/Cas 9 with less risk of off-target DNA breaksKleinstiver, Pattanayak, Prew, Tsai, Nguyen, Zheng, JoungHarvard UniversityCRISPR-Cas9, Gene editing
1 Feb 2016UK scientists authorised to genetically modify human embryos using CRISPR-Cas 9NiakanCrick InstituteCRISPR-Cas9
16 May 2016US scientists publish new base editing technique offering means to alter genome without needing to cleave double-stranded DNA or for a donor DNA templateKomor, Kim, Packer, Zuris, LiuHarvard UniversityCRISPR-Cas9, Gene editing
21 Jun 20162016: NIH gives green light for first clinical trial using gene editing tool CRISPR/Cas 9 to treat patientsJuneUniversity of PennsylvaniaCRISPR-Cas9, Gene editing, Gene therapy, Cancer immunotherapy
Feb 2017US National Academies of Science and Medicinegrant grant green light to proceed with CRISPR in germ-line experiments  CRISPR-Cas9, Gene editing
13 Apr 2017CRISPR shown to be sensitive diagnostic tool for detecting single target of DNA or RNA moleculeAbudayyeh, Bhattacharyya, Collins, Daringe, Donghia, Dy, Essletzbichler, Freije, Hung, Joung, Koonin, Lee, Livny, Myhrvold, Regev, Sabeti, Gootenberg, Verdine, ZhangBroad Institute, Massachusetts Institute of Technology, Harvard University, Howard Hughes Medical Institute CRISPR-Cas9, Gene editing
13 May 2017Research published demonstrating how CRISPR-CAS9 can be used to eliminate HIV in infected mice. Yin, Zhang, Qu, Chang, Putatunda, Xiao, Li, Zhao, Dhai, Qin, Mo, Young, Khalili, HuTemple University, University of Pittsburgh, Sichuan UniversityCRISPR-Cas9, Gene editing
2 Aug 2017Research published demonstrating possibility of editing gene defect in pre-implanted human embryos for preventing inherited heart diseaseHong, Marti-Gutierrez, Park, Mitalipov, Kaul, Kim, Amato, BelmonteOregon Health & Science University, Salk Institute, Center for Genome Engineering, Seoul National University, China National GeneBank,CRISPR-Cas9, Reproduction, Cardiovascular, Gene editing
Sep 2017DNA of human embryos edited using CRISPR-Cas9 to study cause of infertilityFogarty, McCarthy, Snijders, Powell, Kubikova, Blakeley, Lea, Elder, Wamaitha, Kim, Maciulyte, Kleinjung, Kim, Wells, Vallier, Bertero, Turner, NiakanFrancis Crick Instiitute, Cambridge University, Oxford University, Seoul National UniversityCRISPR-Cas9, Gene editing, Reproduction
23 Sep 2017Chinese researchers report correction of gene linked to beta thalassaemia, inherited blood disorder, in human embryos using base editing techniqueLiang, Ching, Sun, Xie, Xu, Zhang, Xhiong, Ma, Liu, Wang, Fang, Songyang, Zhou, HuangSun Yat-sen University, Baylor College of MedicineCRISPR-Cas9, Gene editing, Reproduction
25 Oct 2017New CRISPR technique published for editing RNA Zhang, Cox, Gootenberg, Abudayyeh, B Franklin, Kellner, Essletzbichler, Verdine, Joung, Lander, Belanto, Voytas, RegevMassachusetts Institute of Technology, University of MinnesotaCRISPR-Cas9, Gene editing, RNA
25 Oct 2017Base editing improvements announced for CRISPR technique, providing means to change individual chemical letters of DNA without need to cleave DNAGaudelli, Komor, Rees, Packer, Badran, Bryson, LiuMassachusetts Institute of Technology, Harvard UniversityCRISPR-Cas9, Gene editing
5 Jan 2018Researchers identify pre-existing antibodies targeting CAS9 proteins raising possibility of immune responses undermining utility of CRISPR-Cas9 for gene therapyCharlesworth, Deshpande, Dever, Dejene,Gomez-Ospina, Mantri, Pavel-Dinu, Camarena, Weinberg, PorteusStanford UniversityGene therapy, Gene editing, CRISPR-Cas9
27 Aug 2018First CRISPR-Cas9 clinical trial launched Vertex Pharmaceuticals, CRSIPR TherapeuticsCRISPR-Cas9, Gene therapy
24 Nov 2018First gene-edited babies announced by Chinese scientistJiankuiSouthern University of Science and Technology of ChinaCRISPR-Cas9, Reproduction
14 Dec 2018New gene modification technique (CRISPRa) makes it possible to increase expression of its target geneMatharu, Rattanasopha, Tamura, Maliskova, Wang, Bernard, Hardin, Eckalbar, Vaisse, AhituvUniversity of California San FranciscoCRISPR-Cas9
21 Dec 2018CRISPR-Cas9 editing helped restore effectiveness of first-line chemotherapies for lung cancerKmiec, Bialk, Wang, Hanas Helen F Graham Cancer Center and Research InstituteCRISPR-Cas9, Oncology
23 Jan 2019CRISPR-Cas9 used to control genetic inheritance in miceGrunwald, Gntz, Poplawski, Xu, Bier, CooperUniversity of California San DiegoCRISPR-Cas9, Genetics, Transgenic animals

1 Dec 2015

International Summit on Human Gene Editing met to discuss the scientific, medical, ethical, and governance issues associated with recent advances in human gene-editing research

31 Dec 2015

Gene editiing tool, CRISPR, successfully used to improve muscle function in mouse model of Duchenne muscular dystrophy

6 Jan 2016

US scientists published improved version of CRISPR/Cas 9 with less risk of off-target DNA breaks

1 Feb 2016

UK scientists authorised to genetically modify human embryos using CRISPR-Cas 9

16 May 2016

US scientists publish new base editing technique offering means to alter genome without needing to cleave double-stranded DNA or for a donor DNA template

21 Jun 2016

2016: NIH gives green light for first clinical trial using gene editing tool CRISPR/Cas 9 to treat patients

Feb 2017

US National Academies of Science and Medicinegrant grant green light to proceed with CRISPR in germ-line experiments

13 Apr 2017

CRISPR shown to be sensitive diagnostic tool for detecting single target of DNA or RNA molecule

13 May 2017

Research published demonstrating how CRISPR-CAS9 can be used to eliminate HIV in infected mice.

2 Aug 2017

Research published demonstrating possibility of editing gene defect in pre-implanted human embryos for preventing inherited heart disease

Sep 2017

DNA of human embryos edited using CRISPR-Cas9 to study cause of infertility

23 Sep 2017

Chinese researchers report correction of gene linked to beta thalassaemia, inherited blood disorder, in human embryos using base editing technique

25 Oct 2017

New CRISPR technique published for editing RNA

25 Oct 2017

Base editing improvements announced for CRISPR technique, providing means to change individual chemical letters of DNA without need to cleave DNA

5 Jan 2018

Researchers identify pre-existing antibodies targeting CAS9 proteins raising possibility of immune responses undermining utility of CRISPR-Cas9 for gene therapy

27 Aug 2018

First CRISPR-Cas9 clinical trial launched

24 Nov 2018

First gene-edited babies announced by Chinese scientist

14 Dec 2018

New gene modification technique (CRISPRa) makes it possible to increase expression of its target gene

21 Dec 2018

CRISPR-Cas9 editing helped restore effectiveness of first-line chemotherapies for lung cancer

23 Jan 2019

CRISPR-Cas9 used to control genetic inheritance in mice