2022
DOI: 10.1007/s00018-022-04175-8
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Maybe you can turn me on: CRISPRa-based strategies for therapeutic applications

Abstract: Since the revolutionary discovery of the CRISPR-Cas technology for programmable genome editing, its range of applications has been extended by multiple biotechnological tools that go far beyond its original function as “genetic scissors”. One of these further developments of the CRISPR-Cas system allows genes to be activated in a targeted and efficient manner. These gene-activating CRISPR-Cas modules (CRISPRa) are based on a programmable recruitment of transcription factors to specific loci and offer several k… Show more

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Cited by 21 publications
(12 citation statements)
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“…For this purpose, we focused on “dead” (d)Cas9-VPR, a very potent CRISPRa module with high translational potential 28 . The range of applications of CRISPRa for the treatment of genetic or acquired diseases includes transcriptional activation (transactivation) of silent genes that are functionally equivalent to defective genes 29 . The MYO7A ( USH1B ) gene represents an attractive target for CRISPRa therapy, as it exceeds the capacity of AAV vectors and is associated with Usher syndrome (USH), the most common form of genetic deafblindness.…”
Section: Resultsmentioning
confidence: 99%
“…For this purpose, we focused on “dead” (d)Cas9-VPR, a very potent CRISPRa module with high translational potential 28 . The range of applications of CRISPRa for the treatment of genetic or acquired diseases includes transcriptional activation (transactivation) of silent genes that are functionally equivalent to defective genes 29 . The MYO7A ( USH1B ) gene represents an attractive target for CRISPRa therapy, as it exceeds the capacity of AAV vectors and is associated with Usher syndrome (USH), the most common form of genetic deafblindness.…”
Section: Resultsmentioning
confidence: 99%
“…Many of these disorders, including SMS, are incompatible with gene replacement therapy because the length of disease-causing genes exceeds the payload capacity of AAVs. A promising alternative strategy is transcriptional targeting of the endogenous cis-regulatory elements of haploinsufficient genes ( 25 , 28 , 37 , 38 ), which in principle should benefit SMS patients either carrying Rai1 point mutations or 17p11.2 deletions. Here, we show that mouse Rai1 proximal promoter is accessible to CRISPRa-mediated Rai1 overexpression in vitro and in vivo .…”
Section: Discussionmentioning
confidence: 99%
“…The advent of clustered regularly interspaced short palindromic repeats activation (CRISPRa) system and the discovery of the smaller Staphylococcus aureus CRISPR-associated protein 9 (saCas9) hold great promise for rAAV-mediated, gene size-independent therapy in treating SMS and other disorders associated with genetic forms of obesity, epilepsy, blindness, and muscular dystrophy ( 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ). A common strategy to express Cas9 and single-guide RNAs (sgRNAs) is using dual rAAV systems that could result in low co-infection efficiency ( 28 ). To overcome this challenge, we adapted an “all-in-one” single vector rAAV-CRISPRa system that encodes a sgRNA and a nuclease-deficient saCas9 (sadCas9) fused with the VP64 transcriptional activator ( 25 ).…”
mentioning
confidence: 99%
“…The CRISPRa system is divided into two parts: the sgRNA/Cas9 complex, which plays a targeting role, and the activating structural domain, which enhances transcription. 59 , 321 In general, when performing gene editing, only one sgRNA targeting the target site will be designed. Maeder et al designed sgRNAs at four positions near the transcriptional start site of the target gene to obtain higher gene activation efficiency.…”
Section: Limitations and Challengesmentioning
confidence: 99%