Base editors: development and applications in biomedicine

doi:10.1007/s11684-023-1013-y

Frontiers of Medicine

2023, Vol. 17

Issue (3): 359-387 https://doi.org/10.1007/s11684-023-1013-y

本期目录

Base editors: development and applications in biomedicine

Yanhui Liang^1,^2,³, Fangbing Chen^1,^2,^3,⁴, Kepin Wang^1,^2,^3,⁴, Liangxue Lai^1,^2,^3,⁴(

)

¹. China-New Zealand Joint Laboratory on Biomedicine and Health, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
². Research Unit of Generation of Large Animal Disease Models, Chinese Academy of Medical Sciences (2019RU015), Guangzhou 510530, China
³. Sanya Institute of Swine Resource, Hainan Provincial Research Centre of Laboratory Animals, Sanya 572000, China
⁴. Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China

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Abstract：

Base editor (BE) is a gene-editing tool developed by combining the CRISPR/Cas system with an individual deaminase, enabling precise single-base substitution in DNA or RNA without generating a DNA double-strand break (DSB) or requiring donor DNA templates in living cells. Base editors offer more precise and secure genome-editing effects than other conventional artificial nuclease systems, such as CRISPR/Cas9, as the DSB induced by Cas9 will cause severe damage to the genome. Thus, base editors have important applications in the field of biomedicine, including gene function investigation, directed protein evolution, genetic lineage tracing, disease modeling, and gene therapy. Since the development of the two main base editors, cytosine base editors (CBEs) and adenine base editors (ABEs), scientists have developed more than 100 optimized base editors with improved editing efficiency, precision, specificity, targeting scope, and capacity to be delivered in vivo, greatly enhancing their application potential in biomedicine. Here, we review the recent development of base editors, summarize their applications in the biomedical field, and discuss future perspectives and challenges for therapeutic applications.

Key words： base editing CBE ABE ADAR DdCBE disease model therapeutic application

收稿日期: 2023-02-23 出版日期: 2023-07-28

Corresponding Author(s): Liangxue Lai

引用本文:

. [J]. Frontiers of Medicine, 2023, 17(3): 359-387.
Yanhui Liang, Fangbing Chen, Kepin Wang, Liangxue Lai. Base editors: development and applications in biomedicine. Front. Med., 2023, 17(3): 359-387.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-023-1013-y
https://academic.hep.com.cn/fmd/CN/Y2023/V17/I3/359

Tab.1

Fig.1

Fig.2

Types	Names	Architectures	Modifications	Purposes	Reference
Nuclear base editors, CBE	BE3	rAPOBEC1-nCas9-UGI	Employment of rat APOBEC1 cytosine deaminase	The first active and widely used base editor	[11]
	HF-BE3	rAPOBEC1-HF-nCas9-UGI	Introduction of additional mutations (N497A/R661A/Q695A/Q926A) into nCas9 for a high-fidelity version	Reducing off-target DNA editing	[122]
	BE4	rAPOBEC1-nCas9-2×UGI	An additional UGI	Improving the efficiency and product purity	[134]
	BE4-Gam	Gam-rAPOBEC1-nCas9-2×UGI	Introduction of a bacteriophage Mu protein Gam that binds DNA double stranded breaks (DSBs)	Reducing insertions and deletions (indels)	[134]
	BE4max	rAPOBEC1-nCas9-2×UGI	Codon optimization and modification of nuclear-localization sequence (NLS)	Improving the efficiency	[103]
	YE1-BE3	rAPOBEC1(W90Y/R126E)-nCas9-UGI	Introduction of W90Y/R126E mutations into rAPOBEC1	Reducing DNA and RNA off-target editing and narrowing the editing window	[118,138,139]
	SECURE-BE3	rAPOBEC1(R33A/K34A)-nCas9-UGI	Introduction of single (R33A) or dual (R33A/K34A) mutations into rAPOBEC1	Reducing RNA off-target editing and narrowing the editing window	[119]
	Target-AID	nCas9-PmCDA1-UGI	Employment of PmCDA1 cytosine deaminase	One of the first-generation CBEs	[12]
	hA3A-BE3	hAPOBEC3A-nCas9-UGI	Replacement of rAPOBEC1 with hA3A	Enhancing the efficiency, especially for GC motif and methylated cytidines	[93,118,139]
	BE3(hA3A^R128A)	hAPOBEC3A(R128A)-nCas9-UGI	Introduction of R128A mutation into hA3A	Reducing RNA off-target editing	[118]
	A3A(N57G)-BE3	hAPOBEC3A(N57G)-nCas9-UGI	Introduction of N57G mutation into hA3A	Conferring preference for TCR motif to minimized bystander and reducing DNA and RNA off-target activities	[142]
	hA3A-eBE-Y130F	hAPOBEC3A(Y130F)-nCas9-4×UGI	Introduction of Y130F mutation into hA3A and three additional UGIs	Narrowing the editing window, reducing RNA off-target editing and indels, improving product purity, and reducing toxic effects	[93,95,139]
	A3Bctd-VHM-BE3 or A3Bctd-KKR-BE3	hA3Bctd(T214V/D314H/Y315M)-nCas9-UGI or hA3Bctd (R211K/ R311K/D314R)-nCas9-UGI	Replacement of hA3A with hA3Bctd variant harboring T214V/D314R/Y315M mutations or R211K/ R311K/D314R mutations	Reducing DNA off-target editing and bystander effect to increase the specificity and precision	[262]
	SaBE4	rAPOBEC1-nSaCas9-2×UGI	Replacement of SpCas9 nickase with nSaCas9	Reducing the size and changing targeting scope to NNGRRT	[134]
	dCpf1-BE	rAPOBEC1-dLbCas12a-UGI	Replacement of SpCas9 nickase with dLbCas12a	Changing targeting scope to T-rich PAM sequence	[106]
	nNme2-CBE	rAPOBEC1-nNme2Cas9-2×UGI	Replacement of SpCas9 nickase with nNme2Cas9	Changing targeting scope to N4CC PAM sequence	[107]
	cjCBEmax	rAPOBEC1-nCjCas9-2×UGI	Replacement of SpCas9 nickase with nCjCas9	Reducing the size of CBE	[146]
	VQR-BE3	rAPOBEC1-VQR-nCas9-UGI	Replacement of SpCas9 nickase with VQR-Cas9 nickase variant	Expanding the targeting scope to NGA PAM sequence	[138]
	SaKKH-BE3	rAPOBEC1-KKH-nSaCas9-UGI	Replacement of SpCas9 nickase with KKH-SaCas9 nickase variant	Expanding the targeting scope to NNNRRT PAM sequence and reducing the size	[138]
	xBE3	rAPOBEC1-xCas9-UGI	Replacement of SpCas9 with xCas9(3.7) variant harboring D10A and seven additional mutations (A262T/R324L/S409I/E480K/E543D/M694I/E1219V)	Expanding the targeting scope to NG, GAA, and GAT PAM sequences	[108,263]
	Target-AID-NG	nCas9-NG-PmCDA1-UGI	Replacement of SpCas9 with SpCas9-NG variant harboring D10A and seven additional mutations (R1335V/L1111R/D1135V/G1218R/E1219F/A1322R/T1337R)	Expanding the targeting scope to NG PAM sequence	[109]
	enAsBE	rAPOBEC1-denAsCas12a-UGI	Replacement of dLbCas12a with denAsCas12a variant harboring D908A/E993A/D1235A and three additional E174R/S542R/K548R mutations	Expanding the targeting scope to NTTN, TYCN, and TRTV PAM sequences	[112]
	enCas12a-A3A-Y130F	hAPOBEC3A(Y130F)-denLbCas12a-4×UGI	Replacement of dLbCas12a with denLbCas12a variant harboring D832A/E1006A/D1125A and three additional D156R/G532R/K538R mutations, and replacement of rAPOBEC1 with hA3A-Y130F variant	Improving the efficiency and expanding the targeting scope to NTTN, TYCN, and TRTV PAM sequences	[101]
	SpRY-CBE	rAPOBEC1-nSpRY-2×UGI	Replacement of SpCas9 with SpRY variant harboring D10A and five additional mutations (A61R/L1111R/N1317R/A1322R/R1333P)	Expanding the targeting scope to NRN > NYN PAM sequences	[111]
	hyeA3A-BE4max	rAPOBEC1-Rad51DBD-nCas9-2×UGI	Introduction of single-stranded DNA-binding domain from Rad51 protein	Improving the efficiency and widening the editing window	[104]
	TaC9-CBEYE1	TALE-rAPOBEC1(W90Y/R126E); UGI-nCas9-UGI	Fusion of cytosine deaminase rAPOBEC1 to TALE array and UGI to nCas9, separately, and introduction of W90Y/R126E into rAPOBEC1	Reducing DNA and RNA off-target editing	[124]
	ABE-P48R-UGI	TadA*7.10(P48R)-nCas9-2×UGI	Introduction of P48R mutation into TadA*7.10 and addition of two UGIs	Engineering ABE to a TC-specific cytosine base editor and reducing bystander editing	[128]
	TadCBE	TadA-CD variant-nCas9	Introduction of additional mutations into TadA*8e to confer cytidine deaminase- specific activity	Engineering ABE to a cytosine base editor, reducing the size, and reducing DNA and RNA off-target editing	[53]
	Td-CBEmax	TadA*8e(E27R)-nCas9-2×UGI	Introduction of E27R mutation into TadA*8e and addition of two UGIs	Engineering ABE to a CBE with reduced off-target and narrow editing window	[48]
	CBE-T	TadC-nCas92×UGI	Introduction of mutations into TadA*8.20, resulting TadC variants	Engineering ABE8s to a compact CBE with reduced DNA off-target	[54]
	d12fCBEs-8e(GGATY)	TadA*8e(GGATY)-dUn1Cas12f1	Introduction of V28G/A48G/I49A/V82T/N108Y mutations into TadA*8e and employment of miniature Un1Cas12f1 ortholog with D326A/D510A mutations	Engineering a compact, precious and specific CBE with TadA variant	[130]
Nuclear base editors, ABE	ABE7.10	ecTadA-TadA*7.10-nCas9	Employment of heterodimeric ecTadA-TadA*7.10 adenine deaminase	The first active and widely used ABE	[13]
	ABEmax	ecTadA-TadA*7.10-nCas9	Codon optimization and modification of nuclear-localization sequence (NLS)	Improving the efficiency	[103]
	ABEmaxAW	ecTadA(E59A)-TadA*7.10(V106W)-nCas9	Introduction of E59A mutation into ecTadA and V106W mutation into TadA*7.10	Reducing RNA off-target editing	[120]
	ABE7.10^F148A	ecTadA(F148A)-TadA*7.10(F148A)-nCas9	Introduction of F148A mutation both into ecTadA and TadA*7.10	Reducing RNA off-target editing	[118]
	SECURE-ABE	TadA7.10(K20A/R21A)-nCas9 or TadA7.10(V82G)-nCas9	Removal of the wild-type ecTadA domain and introduction of K20A/R21A or V82G mutations into TadA*7.10	Reducing RNA off-target editing, self-editing, and the size	[44]
	SaKKH-ABE	ecTadA-TadA*7.10-KKH-nSaCas9	Replacement of SpCas9 nickase with KKH-SaCas9 nickase variant	Reducing the size and expanding targeting scope to NNNRRT	[173]
	xABE	ecTadA-TadA*7.10-xCas9	Replacement of SpCas9 with xCas9(3.7) variant harboring D10A and seven additional mutations (A262T/R324L/S409I/E480K/E543D/M694I/E1219V)	Expanding the targeting scope to NG, GAA, and GAT PAM sequences	[108,263]
	VQR-ABE	ecTadA-TadA*7.10-VQR-nCas9	Replacement of SpCas9 nickase with VQR-Cas9 nickase variant	Expanding the targeting scope to NGA PAM sequence	[173]
	SpRY-ABE	ecTadA-TadA*7.10-nSpRY	Replacement of SpCas9 with SpRY variant harboring D10A and five additional mutations (A61R/L1111R/N1317R/A1322R/R1333P)	Expanding the targeting scope to NRN>NYN PAM sequences	[111]
	ABE8e	TadA*8e-nCas9	Removal of the wild type ecTadA domain and evolvement of TadA7.10 to TadA8e	Improving the efficiency and reducing the size	[99]
	SaABE8e	TadA*8e-nSaCas9	Replacement of SpCas9 nickase with nSaCas9	Reducing the size and changing targeting scope to NNGRRT	[99]
	LbABE8e	TadA*8e-dLbCas12a	Replacement of SpCas9 nickase with dLbCas12a	Changing targeting scope to T-rich PAM sequence	[99]
	enCas12a-ABE8e-V106W	TadA*8e(V106W)-denLbCas12a	Replacement of SpCas9 nickase with denLbCas12a variant and introduction of V106W mutation into TadA*8e	Improving the efficiency, expanding the targeting scope to NTTN, TYCN, and TRTV PAM sequences, and reducing RNA off-target editing	[101]
	cjABE8e	TadA*8e-nCjCas9	Replacement of SpCas9 nickase with nCjCas9	Reducing the size of ABE	[144–146]
	ABE8eWQ	TadA*8e(V106W/D108Q)-nCas9	Introduction of V106W/D108Q mutations into TadA*8e	Reducing cytosine deamination activity of TadA and reducing RNA off-target editing	[128]
	d12fABE-8e	TadA*8e-dUn1Cas12f1	Replacement of SpCas9 with miniature Un1Cas12f1 ortholog with D326A/D510A mutations	Reducing the size and changing targeting scope to TTTR PAM sequence	[130]
	TaC9-ABE	ecTadA-TadA*7.10-TALE; nCas9	Fusion of heterodimeric ecTadA-TadA*7.10 to TALE	Eliminating Cas9-dependent off-target editing	[123]
	ABE9	TadA*8e(N108Q/L145T)-nCas9	Introduction of N108Q/L145T mutations into TadA*8e	Narrowing the editing window	[140]
Nuclear base editors, CGBE	CGBE1	eUNG-rAPOBEC1(R33A)-nCas9	Removal of UGI, introduction of eUNG, and introduction of R33A mutation into rAPOBEC1	Engineering a C-to-G base editor	[20,46]
	GBE	rAPOBEC1-nCas9-UNG	Removal of UGI and introduction of eUNG	Engineering a C-to-G base editor	[19,46]
	CGBE(XRCC1)	rAPOBEC1-nCas9-XRRCC1	Removal of UGI and introduction of DNA repair protein XRRCC1	Engineering a C-to-G base editor	[45]
	SpRY-GBE	rAPOBEC1-nSpRY-UNG	Replacement of SpCas9 with SpRY variant harboring D10A and five additional mutations (A61R/L1111R/N1317R/A1322R/R1333P)	Expanding the targeting scope to NRN > NYN PAM sequences	[47]
	ABE-P48R	TadA*7.10(P48R)-nCas9	Introduction of P48R mutation into TadA*7.10	Engineering ABE to a TC-specific GBE and reducing bystander editing	[128]
	Td-CGBE	TadA*8e(N46L)-nCas9	Introduction of N46L mutation into TadA*8e	Engineering ABE8e to a smaller CGBE with narrow editing window and reduced off-target	[48]
Nuclear base editors, AYBE	AYBE	TadA*8e-nCas9-MPG	Fusion of a human MPG protein to the C- terminus of nCas9	Engineering ABE to new base editor for A-to-C and A-to-T transversion editing	[21]
Nuclear base editors, dual-deaminase base editor	STEME-1	hAPOBEC3A-ecTadA-TadA*7.10-nCas9-UGI-CaMV terminator	Combination of ABE and CBE	Simultaneous dual-base editing for targeted and random mutagenesis	[22]
	A&C-BEmax	rAPOBEC1-ecTadA-TadA*7.10-nCas9-2×UGI	Combination of ABE and CBE	Simultaneous C-to-T and A-to-G conversions at the same target site	[41]
	SPACE	TadA*7.10(V82G)-nCas9-PmCDA1-2×UGI	Combination of miniABE and CBE	Simultaneous C-to-T and A-to-G conversions at the same target site and reducing RNA off-target editing	[42]
	Target-ACEmax	TadA*7.10-nCas9-PmCDA1-UGI	Combination of miniABE and CBE	Simultaneous C-to-T and A-to-G conversions at the same target site	[43]
	ACBE	ecTadA-TadA*7.10-nCas9-PmCDA1-UGI	Combination of ABE and CBE	Simultaneous C-to-T and A-to-G conversions at the same target site	[23]
	CABE-RY	hAPOBEC3A(Y130F)- TadA*8e(V106W)-nCas9-2×UGI	Combination of ABE and CBE, introduction of Y130F into hA3A and V106W into TadA*8e, and employment of SpRY variant	Improving the dual-base editing efficiency, reducing RNA off-target editing, and expanding targeting scope	[51]
	TadDE	TadA-dual variant-nCas9	Introduction of additional mutations into TadA*8e to confer both C-to-T and A-to-G editing activity	Engineering ABE to a dual base editor and reducing the size	[53]
	CABE-T	TadAC-nCas9-2×UGI	Introduction of mutations into TadA*8.20, resulting TadAC variants and addition of two UGIs	Engineering ABE8s to a compact dual base editor with enhanced efficiency and reduced DNA off-target	[54]
	miniAGBE-4	hAPOBEC3A-TadA*8e(V106W)-nCas9	Combination of ABE and miniGBE	Simultaneous dual-base editing for saturated mutagenesis	[24]
Mitochondrial DNA base editors	DdCBE	MTS-TALE-Split-DddA_tox half-UGI; MTS-TALE-Split-DddA_tox half-UGI	Employment of double-strand DNA cytosine deaminase DddA_tox	The first active and widely used mitochondrial base editor	[26]
	ZFD	MTS-ZFP-Split-DddA_tox half-UGI; MTS-ZFP-Split-DddA_tox half-UGI	Replacement of TALE array with ZFP array	Reducing the size and immunogenicity	[66,68]
	mDdCBE	MTS-TALE-DddA_tox full variant-UGI	Fusion of the full-length DddA_tox variant to a single TALE array	Reducing the size	[67]
	sTALED	MTS-TALE-Split-DddA_tox half-TadA*8e; MTS-TALE-Split-DddA_tox half	Introduction of TadA*8e and removal of UGI	The first mitochondrial base editor for A-to-G editing	[27]
	dTALED	MTS-TALE- DddA_tox full variant; MTS-TALE- TadA*8e	Employment of catalytically inactive full-length DddA_tox variant	Reducing mitochondrial DNA off-target effect	[27]
	mTALED	MTS-TALE-TadA*8e-DddA_tox full variant	Fusion of TadA*8e and catalytically inactive full-length DddA_tox variant to a single TALE array	Reducing the size	[27]
RNA base editors	REPAIR	dCas13b-ADAR2_DD	Fusion of dCas13b to ADAR2_DD	The first CRISPR/Cas-based RNA base editor for A-to-I editing	[14]
RNA base editors	RESCUE	dCas13b-evoADAR2_DD	Engineering the adenine deaminase domain of ADAR2 into a cytidine deaminase	The first CRISPR/Cas-based RNA base editor for C-to-U editing, while retaining A-to-I activity	[25]
	CURE	dCas13b-hAPOBEC3A(Y132D) or dCasRx-L-hAPOBEC3A(Y132D)-dCasRx-R	Fusion of hAPOBEC3A(Y132D) to the C-terminus of dCas13b or insertion of hAPOBEC3A(Y132D) into a flexible loop on dCasRx	Engineering a C-to-U RNA base editor without A-to-I activity	[78]
	REWIRE	PUF-ADARDD or hAPOBEC3A-PUF	Fusion of PUF domain with the deaminase domain of ADAR or fusion of PUF domain with hA3A	Engineering a guide-RNA-free A-to-I or C-to-U RNA base editor	[79]
Prime editors	PE2	nCas9(H840A)-M-MLV RT variant; pegRNA	Fusion of nCas9(H840A) with M-MLV RT variant harboring D200N/L603W/T330P/T306K/W313F mutations, and engineering a pegRNA	Enabling all types of base editing, including substitute, short insertion, and deletion	[28]
	PE3	nCas9(H840A)-M-MLV RT variant; pegRNA; nsgRNA	Introduction of an additional nsgRNA to nick the non-edited strand	Improving the efficiency	[28]
	HOPE	nCas9(H840A)-M-MLV RT variant; S-pegRNA; AS-pegRNA	Employment of paired pegRNAs to target both sense and antisense DNA strand	Improving the efficiency and product purity	[91,92,264–267]
	hyPE2	nCas9(H840A)-Rad51DBD-M-MLV RT variant; pegRNA	Introduction of single-stranded DNA-binding domain from Rad51 protein	Improving the efficiency	[87]
	PE4	nCas9(H840A)-M-MLV RT variant; MLH1dn; pegRNA	Co-expression of MLH1dn variant in PE2 system	Improving the efficiency	[85]
	PE5	nCas9(H840A)-M-MLV RT variant; pegRNA; nsgRNA	Co-expression of MLH1dn variant in PE3 system	Improving the efficiency	[85]
	PE2-SpRY	nSpRY(H840A)-M-MLV RT variant; pegRNA	Replacement of SpCas9 nickase with SpRY nickase variant	Expanding the targeting scope	[268]
	Split-intein-PE2	nCas9(H840A)-N-intein-N; intein-C-nCas9(H840A)-C-RT variant; pegRNA	Splitting PE2 with intein	Facilitating delivery via viral vectors	[86,269]
	Split-PE2	nCas9(H840A); M-MLV RT variant; pegRNA	Split nCas9 and reverse transcriptase	Facilitating engineering and delivery via viral vectors	[270]

Tab.2

Fig.3

Tab.3

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