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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 69-76

Clustered regularly interspaced short palindromic repeats-Cas9 gene therapy: The top 50 most-cited papers


1 College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
2 College of Medicine, Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
3 Department of Family Medicine, King Saud Medical City, Riyadh, Saudi Arabia

Date of Web Publication2-Apr-2019

Correspondence Address:
Jude Howaidi
College of Pharmacy, Princess Nourah Bint Abdulrahman University, Postal Code 11671, Al Imam Abdullah Ibn Saud Ibn Abdul Aziz Road, King Khalid International Airport, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_52_18

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  Abstract 


Background: Clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) is a gene-editing technique that creates advancement in biomedical technology. It is a form of gene alteration method that was investigated and examined from Streptococcus pyogenes dependable on Cas9 nuclease enzyme through microbiological and genetic examination. This system consists of a nucleic acid, RNA, specifically guide RNA (gRNA), and a nuclease enzyme, Cas9. The potential implications of CRISPR/Cas9 include cancer, cystic fibrosis, familial hypercholesterolemia, and Duchenne's muscular dystrophy. Objective: The objective was to show the most impactful publications through a bibliometric analysis of the top 50 most-cited papers regarding the topic of CRISPR/Cas9 gene-editing tool. Methods: The most-cited research articles relative to CRISPR Cas9 were collected using Scopus. The order of the most-cited papers was conducted by categorizing the studies in an ordinal manner from the most-cited to the least-cited studies. The studies were stratified by selecting the top 50 most-cited papers with the title “CRISPR Cas9.” Results: A number of 2230 research papers regarding CRISPR Cas9 were retrieved. 42% of the papers from the top 50 most-cited papers were published in 2014. The total citation count for each of the top 50 studies ranged from 183 to 1824, and the mean number of citations was 420. The first five articles were cited more than 1000 times and the remaining articles were cited more than 100 times. The journal “Nature” has published the most studies relevant to CRISPR Cas9 with a total of 23 studies, Cell with 8 studies, followed by Science and Nucleic Acids with 4 studies published and Genetics with 2 and the remaining journals with one publication each. Conclusion: It is clear that the future of CRISPR Cas9 is promising as demonstrated by the highly impactful studies in the topic with high citation counts in a relatively short period of time after publication.

Keywords: Clustered regularly interspaced short palindromic repeats-Cas9, gene therapy, gene editing


How to cite this article:
Howaidi J, Howaidi A, Howaidi F. Clustered regularly interspaced short palindromic repeats-Cas9 gene therapy: The top 50 most-cited papers. J Nat Sci Med 2019;2:69-76

How to cite this URL:
Howaidi J, Howaidi A, Howaidi F. Clustered regularly interspaced short palindromic repeats-Cas9 gene therapy: The top 50 most-cited papers. J Nat Sci Med [serial online] 2019 [cited 2019 Apr 23];2:69-76. Available from: http://www.jnsmonline.org/text.asp?2019/2/2/69/250746




  Introduction Top


Gene therapy was first hypothesized in the 1970s. The notion was initiated by Rogers, who proposed that a defected gene in a DNA can be replaced by a well-functioning DNA that has been exogenously synthesized.[1] In 1972, Friedmann and Roblin conceptualized gene therapy in a review titled, “Gene therapy for human genetic disease?”[2] Over the years, gene therapy has advanced and evolved through the conduction of clinical trials involving defective genes that lead to vast investments and successes in biotechnology.[3],[4],[5]

Clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) is a gene-editing technique that creates advancement in biomedical technology. It is a form of gene alteration method that was investigated and examined from Streptococcus pyogenes dependable on Cas9 nuclease enzyme through microbiologic and genetic examinations.[6],[7] This system consists of a nucleic acid, RNA, specifically guide RNA (gRNA), and a nuclease enzyme, Cas9. The aim of this system is to manipulate a DNA's sequencing in the process of either removing or adding parts of the genome.[8],[9],[10] Cas9 operates as a cutting tool in which it cuts the DNA pair at a site previously identified by gRNA. gRNA, on the other hand, has a predetermined sequence that is part of the complete structure of the RNA; this sequence is the major determinant for identification and binding on the DNA sequence in the genome that requires editing. The sequence of the gRNA consists of RNA bases that complement and are in parallel to the target DNA sequence. The pattern by which this system follows to alter DNA sequencing is initially through the guidance of gRNA. gRNA's predetermined sequence binds to a specific site on the DNA strands; shortly thereafter, Cas9 cuts the target location identifiably amplified by gRNA that eventually leads to the addition or removal of DNA segments.[10],[11],[12],[13],[14]

CRISPR/Cas9 is currently being studied in animal models to correctly reverse numerous diseases and conditions. It has the potential to be utilized routinely in humans.[15],[16] The diseases in which CRISPR/Cas9 can cure are genetically characterized; they have a genetic linkage in the manifestation of a disease. The potential implications of CRISPR/Cas9 include cancer, cystic fibrosis (CF), familial hypercholesterolemia, and Duchenne's muscular dystrophy (DMD).[17],[18],[19],[20],[21] In addition, the system has the possibility to treat hemoglobinopathies such as thalassemia's and sickle cell anemia.[22],[23] Through further evaluation and investigation by geneticists and researchers, CRISPR/Cas9 has the implication of treating infectious diseases as well such as human immunodeficiency virus (HIV) and hepatitis B.[24],[25],[26],[27]

Currently, CRISPR/Cas9 is being evaluated for transition from preclinical trials to clinical trials.[9] Researches on CRISPR/Cas9 have risen dramatically due to its promising potential in treating conditions that are often untreatable.[28],[29] Scientists and geneticists are empowering this form of gene editing through research and believe that its importance and implication in health are pivotal.[30],[31]

CRISPR/Cas9 gene therapy is an emerging gene-editing tool that needs to be highlighted and elucidated through research. This form of gene therapy is an extraordinary approach in medicine since certain diseases are regarded as incurable and are merely managed and controlled through medications utilized long term with potentially harmful side effects that need to be avoided and managed, in addition to the repeated monitoring plan required for both the disease and medications. However, CRISPR/Cas9 has the implication to cure diseases that are considered incurable. This gene-editing technique would serve as a miraculous method for disease curability in clinical setting in the future; therefore, CRISPR/Cas9 requires further researching to emphasize its importance through supporting the findings in current preclinical trials and potential subsequent clinical trials.

The purpose of this research is to show the most impactful publications through a bibliometric analysis of the top 50 most-cited papers regarding the topic of CRISPR/Cas9 gene-editing tool.


  Methods Top


Data retrieval

The most-cited research articles relative to CRISPR/Cas9 were collected using Scopus through July 2018. Scopus is one of the largest databases which show abstracts and citations. The literature is peer reviewed. The database enables the search from a variety of fields and areas of discipline. We used Scopus search tool to identify indexed articles. Articles were identified by searching for titles with the term “CRISPR Cas9” in the search tool to retrieve the researches relative to the topic. The order of the most-cited papers was conducted by categorizing the studies in an ordinal manner from the most cited to the least-cited studies; in addition, the studies were stratified by selecting the top fifty most-cited papers with the title “CRISPR Cas9” among the 2230 researches.

The studies retrieved were assorted according to the title, number of citations, year of publication, journal, first authors, subject area, in addition to country of origin. The papers selected among the top 50 most-cited papers must be published between 2011 and 2017; in addition, the type of papers that were specifically selected for retrieval was original articles, review articles, systematic reviews, and letters.


  Results Top


A number of 2230 research papers regarding CRISPR Cas9 were retrieved through the utilization of the search tool. The top 50 studies relative to CRISPR Cas9 are presented in [Table 1]. The top 50 studies were published between 2013 and 2016. [Table 2] shows the frequency distribution between the years of publication for the top 50 research papers. Forty-two percent of the papers from the top 50 most-cited papers were published in 2014. The total citation count for each of the top 50 studies ranged from 183 to 1824, and the mean number of citations was 420. The first five articles were cited more than 1000 times and the remainders were cited more than 100 times. [Table 3] shows the papers that are cited more than 1000 times.
Table 1: Top 50 studies on clustered regularly interspaced palindromic repeats Cas9 from Scopus

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Table 2: Frequency distribution of the years of publication of the top 50 researches

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Table 3: Research papers that are cited more 1000 times

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The journals in which the top 50 research papers were published are presented in [Table 4]. The journal Nature has published the most studies relevant to CRISPR Cas9 with a total of 23 studies, Cell with eight studies, followed by Science and Nucleic Acids with four studies published and Genetics with two. Development, Scientific Reports, Plant Biotechnology, Molecular, Biotechnology Advances, eLife, Genome Research, Protein and Cell, Stem Cell Reports have each published one research paper on CRISPR Cas9.
Table 4: Journals in which the top fifty studies were published (ranked according to the number of studies)

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The types of document utilized among the top 50 studies on CRISPR Cas9 were articles, reviews, and letters. Articles comprised 45 (90%) of the top 50 most-cited papers. Reviews comprised 4 (8%), and one publication was implemented in the form of a letter (2%). [Table 5] shows the total number of studies for each document type.
Table 5: Total number for types of documentation

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Authors with first author publications are presented. Ran F. A., Shalem O., Kleinstiver B. P., Gratz S. J., Doench J. G. have two publications each within the top 50 most-cited papers on CRISPR/Cas9.


  Discussion Top


In our study, we summarize the top 50 most-cited research papers relative to CRISPR/Cas9. We used a bibliometric approach to demonstrate and analyze the papers to showcase not merely the quality but also the quantity of the papers in a comprehensive, measurable interpretation for written publications.[82] We believe that a bibliometric analysis is suited and is applicable to our study, considering our focus regarding a numerical order of a group of studies relative to CRISPR/Cas9.

Through our search, we have managed to retrieve a total number of 2230 regarding CRISPR/Cas9. Not surprisingly, the number of studies retrieved is abundant; we believe that this accounts for the novelty of this form of gene-editing technique that gained consideration in 2011 following its investigation and biomedical analysis which proceeded in the collaboration of multiple scientists and geneticists in the exploration of CRISPR/Cas9.[83],[84] Through further analysis, we narrowed the studies by designating the articles according to the number of citations. We distinguished that the initial five studies were cited more than 1000 times;[32],[33],[34],[35],[36] in contrast, the remaining 45 studies were cited more than 100 times. The citation rate for each study varied, and there seems to be a significant difference between citation counts. The observed difference is noticed between the 6th paper in comparison to the 7th paper from the top 50 articles. In relation to time, the citation rate appears to increase with previous articles such as those published in 2013 as well as 2014.

Authors with first author mentioning within the top 50 most-cited papers include Ran et al., with two papers published within the list regarding CRISPR/Cas9.[32],[35] In addition, the author's publications are within the top 10 most-cited papers ranking 1st and 4th on the list, with each article having 1824 and 1202 citations, respectively. Shalem et al., another author with two publications on CRISPR/Cas9 in the top 50 most-cited papers. Similarly, Shalem et al.'s paper “Genome-scale CRISPR-Cas9 knockout screening in human cells” ranked 5th on the top 50 list with 1197 citations.[36] The author's second paper titled “High-throughput functional genomics using CRISPR-Cas9” was the 24th most-cited paper among the list. It managed to be cited 302 times.[55] Kleinstiver et al. have two papers.[39],[47] Their paper was 8th on the list with 499 citations, in addition to their second paper which has 388 citations that did not seem to differ significantly from the other paper published by the author. His second paper was ranked 16th. Moreover, the papers titled “Genome engineering of Drosophila with the CRISPR RNA-guided Cas9 nuclease” and “Highly specific and efficient CRISPR/Cas9-catalyzed homology-directed repair in Drosophila” were both published by author Gratz et al., whom their two publications managed to be cited 392 and 190 times, respectively. Finally, Doench et al. also have two publications regarding CRISPR/Cas9.[48],[58] Their papers are 17th and 27th on the list with 376 and 275 citations, respectively.

The top 50 most-citied studies were published between 2013 and 2016. Most of the studies within the top 50 most-cited papers were published in 2014 (42%). We believe that this in part due to the introduction of CRISPR/Cas9 gene therapy in the field of biotechnology, as well as the demonstration of its relevance and abundant role through the implementation of CRISPR/Cas9 gene editing in animal and plant models, that thereafter, have caused a rise in questioning and produced ideations that led to further investigation and amplification of its importance in treating genetically linked disorders.[85],[86],[87],[88] Among the top 50 studies, the majority of the papers that were published in 2013 were conducted on animal and plant models. The nonhuman models in which gene alteration was observed were mice,[35],[41],[45],[68] nematodes,[43] Drosophila,[46],[53] and zebrafish,[80] as well as plant models such as Arabidopsis, tobacco plant, sorghum, and rice.[50]

As aforementioned, the diseases that have the potential for treatment are genetically linked. Among the top 50 most-cited studies, the diseases that were stated include CF, cancer, muscular dystrophy, cataracts, and HIV. Cancer treatment using CRISPR/Cas9 was observed in animal models in vivo that led to reproducibility of in vitro human oncogenic analysis which showed promising results.[44],[89],[90] On the other hand, cataract observed in mice had a genetic link to the CRYGC gene that further led to the investigation of the integration of CRISPR/Cas9 for disease reversal.[68] Moreover, HIV-1in vitro analysis using CRISPR/Cas9 has also been demonstrated and has shown to successfully manage the disruption of HIV-1 expression through the incorporation of CRISPR/Cas9.[91] Muscular dystrophy is a disorder that is reputed to be incurable.[92] However, in a recent study which is obtainable within the top 50 list, it showcased a connection between CRISPR/Cas9 gene editing and the prevention of DMD in vivo animal model. The study concluded that there is potential for a preventative approach in using CRISPR/Cas9 in DMD in humans.[93] CF is linked to CFTR protein, which is required to be genetically expressed to prevent disease manifestations. In CF, this portion is defected which would ultimately lead to CF.[94] The role of CRISPR/Cas9 in CF was demonstrated that the mutation in the protein was successfully corrected using the CRISPR/Cas9 system in vitro investigation through human oncogenic analyses.[41] Through our evaluation of the top 50 most-cited papers, it is apparent that preclinical trials in nonhuman models as well as human in vitro genome analysis have proven that CRISPR/Cas9 is effective in altering the genetic coding of multiple diseases which indicates the curability of those diseases; therefore, CRISPR/Cas9 gene therapy has the potential for clinical trial conduction in the future due to the promising outcomes seen in both in vivo and in vitro analyses.

CRISPR/Cas9 gene therapy has come along way since the idea of DNA alteration has been hypothesized in the 1970s.[1] The immense research in terms of gene editing has been showing a promising future for multiple conditions that weigh heavily from a psychological and physical standpoint, in addition to an economic perspective. The top 50 most-cited papers are pivotal to the rise of CRISPR/Cas9 gene therapy as they aid and support the performance of this method of gene alteration; in addition, they add value to this scope of medicine by their implementation of CRISPR/Cas9 gene altering tool on animal models which showed successful and efficient outcomes.[35],[43],[46],[80] In addition, the most valuable supportive measure of the utilization of CRISPR/Cas9 that would support its endorsement in the future on humans is its implementation through in vitro human genome analyses.[44],[91] The citation count for the top 50 papers is steadily and continuously increasing, which is indicative of CRISPR/Cas9 gene therapy's positive prominence in the past 5 years.


  Conclusion Top


It is evident from the literature search that the future of CRISPR Cas9 is promising as demonstrated by the highly impactful studies in the topic with high citation counts in a relatively short period after publication. With its potential to treat a wide array of diseases and conditions, it is safe to say that research on this topic will improve and increase in prospective advances in biomedical technology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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