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      In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Within less than a decade since its inception, CRISPR-Cas9-based genome editing has been rapidly advanced to human clinical trials in multiple disease areas. Although it is highly anticipated that this revolutionary technology will bring novel therapeutic modalities to many diseases by precisely manipulating cellular DNA sequences, the low efficiency of in vivo delivery must be enhanced before its therapeutic potential can be fully realized. Here we discuss the most recent progress of in vivo delivery of CRISPR-Cas9 systems, highlight innovative viral and non-viral delivery technologies, emphasize outstanding delivery challenges, and provide the most updated perspectives.

          Graphical abstract

          CRISPR-Cas9 genome editing technology has the potential to provide life changing cures to many patients. Safe and efficient delivery vectors are the key to the broad clinical success.

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Fernando P Polack, Stephen J. Thomas, Nicholas R.E. Kitchin … (2023)
          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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            A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.

            Martin Jinek, Krzysztof Chylinski, Ines Fonfara … (2012)
            Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
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              Multiplex genome engineering using CRISPR/Cas systems.

              Le Cong, F. Ran, David T. Cox … (2013)
              Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
              Article 0 comments Cited 2906 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Hongwei Zhang
                Journal
                Journal ID (nlm-ta): Acta Pharm Sin B
                Journal ID (iso-abbrev): Acta Pharm Sin B
                Title: Acta Pharmaceutica Sinica. B
                Publisher: Elsevier
                ISSN (Print): 2211-3835
                ISSN (Electronic): 2211-3843
                Publication date PMC-release: 26 May 2021
                Publication date (Print): August 2021
                Publication date (Electronic): 26 May 2021
                Volume: 11
                Issue: 8
                Pages: 2150-2171
                Affiliations
                [a ]Department of Pharmaceutical Sciences, School of Pharmacy–Boston, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
                [b ]Department of Endocrinology, Tangshan Hospital of Traditional Chinese Medicine, Tangshan 063000, China
                [c ]Department of Chemistry, Brandeis University, Waltham, MA 02454, USA
                Author notes
                [∗ ]Corresponding author. Tel.: +1 6177322969; fax: +1 6177322228. hongwei.zhang@ 123456mcphs.edu
                [†]

                These authors made equal contributions to this work.

                Article
                Publisher Item ID: S2211-3835(21)00186-6
                DOI: 10.1016/j.apsb.2021.05.020
                PMC ID: 8424283
                PubMed ID: 34522582
                SO-VID: 427cd627-a263-483d-9467-9ea96830f024
                Copyright © © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 22 January 2021
                Date revision received : 21 March 2021
                Date accepted : 30 March 2021
                Categories
                Subject: Review

                Keywords: crispr,cas9,genome editing therapy,lnp,nanoparticle,aav,lentivirus,in vivo
                Data availability:
                Keywords: crispr, cas9, genome editing therapy, lnp, nanoparticle, aav, lentivirus, in vivo

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