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Table 1 Embryo-based genome editing reports in NHPs with an objective towards creating models of human disease

From: CRISPR/Cas9 genome editing to create nonhuman primate models for studying stem cell therapies for HIV infection

References

Species

Disease

Model

Gene

CRISPR Construct

No. CRISPR/Cas9 microinjected zygotes

No. embryos transferred, surrogates, pregnancies

Offspring Produced

% Offspring

Edited

% edited live offspring/ embryos transferred

Notable editing outcomes

Niu et al. [29], Chen et al. [21], Kang et al. [12]

C

Adrenal hypoplasia congenita, hypogonadotropic hypogonadism

DAX1*

5 sgRNAs

Cas9 mRNA

186

83

29

10

6 live

13 miscarriage

NS*

NS*

DAX1 mutations observed in several tissues including testis

Germline acquisition of edits reported by Chen et al. 2015

Chen et al. [30], Wang et al. [86]

R

Duchenne muscular dystrophy (DMD)

DMD

2 sgRNAs Cas9 mRNA

NS

179

59

17

14 live

4 stillborn

8 miscarriages

61.1

5.03

WGS revealed no off-target editing

Wan et al. [26]

C

Tumorigenesis

p53

sgRNA

Cas9 mRNA

108

62

13

4

3 live

2 miscarriages

40

3.2

Biallelic editing reported in 1 live infant

Tu et al. [25]

C

NS

ASPM

2 sgRNAs

Ubi-Cas9 mRNA

NS

178

47

11

6 live

66.7

2.25

A ubiquitin-tagged Cas9 may reduce but not eliminate mosaicism

Zuo et al. [27]

C

Paroxysmal kinesigenic dyskinesia

PRRT2

1 or 3 sgRNAs

Cas9 mRNA

NS

84

NS

NS

6 live

6 stillborn

58.3

5.95

A complete knock-out was produced by targeting with 3 sgRNAs

Zhao et al. [33, Tu et al. [91]

C

Autism Spectrum Disorder

SHANK3

2 sgRNAs Cas9 mRNA

NS

116

37

3

1 live

1 stillbirth

1 miscarriage

100

0.86

An 11.5 kb deletion between the two targeted exons of SHANK3 detected in the miscarried fetus

Zhang et al. [13]

C

SIRT6-null

SIRT6

sgRNA

Cas9 mRNA

98

48

12

4

3 live

1 miscarriage

75

6.25

Biallelic editing observed in three offspring

Yang et al. [14]

R

Parkinson’s Disease

PINK1

2 sgRNAs Cas9 mRNA

158

87

28

11

11 live

4 miscarriages

73.3

5.06

A ~ 7.2 kb deletion in PINK1 detected in three offspring

Zhou et al. [22]

C

Autism Spectrum Disorder

SHANK3

2 sgRNAs

NS

178

26

12

9 live

9 deceased

55.5

(of live)

2.80

Three F1 edited heterozygous SHANK3-mutants confirms germline transmission of edits

Qiu et al. [88]

C

circadian-related disorders

BMAL1

1–2 sgRNAs

Cas9 mRNA

NS

88

31

10

8 live

2 miscarriages

60

6.82

Three live knock-out infants and two mosaic generated with no off-target editing

Tsukiyama et al. [28]

C

Polycystic kidney disease

PKD1

sgRNA

Cas9 mRNA

403

86

86

29

14 live

8 stillbirths

7 miscarriages

100

16.28

Reported highest proportion of live edited offspring and use of an allele-specific targeting approach

Schmidt et al. [80]

MCM

HIV-resistance

CCR5

2 sgRNA Cas9 RNP

NS

50

6

0

0 live

0

0

Whole embryo and blastomere genotyping resulted in 23–37% bilallelic editing of CCR5

Chen et al. [92]

C

Parkinson’s Disease

PINK1

2 sgRNA

Cas9-D10A mRNA

126

51

25

6

4 live

75

5.88

First report of targeted-offspring by Cas9-D10A with an editiing efficiency of 9.1–100%

Wang et al. [42]

C

Hutchinson-Gilford progeria syndrome

LMNA

gRNA

Base editor mRNA

86

41

11

6

5 live

1 miscarriage

83.3

12.20

First report of live edited offspring generated via base-editors; offspring carried a precise C-T conversion in LMNA

  1. Live births indicate those born alive, although infant death may have occurred hours to months after birth
  2. C cynomolgus macaque, MCM Mauritian cynomolgus macaque, R rhesus macaque, NS not specified
  3. *Multiplex editing of three genes including DAX1; total number of DAX1-edited offspring is not clear from the three reports describing these offspring