Table 1.
Current gene correction treatments for many genetic diseases.
| Disease | Target gene | Type of mutation | Gene recovery strategy |
|---|---|---|---|
| Achondroplasia | Fgfr3 | c.1120 G > A (p.G374R) | HDR (ssODN)45 |
| Alzheimer’s disease (AD) | PSEN2 | c.422 A > T (p.N141I) | HDR (ssODN)46 |
| APOE | ApoE4 Arg158a | CBE71 | |
| Amyotrophic lateral sclerosis (ALS) | SOD1 | c.281 G > C (G94A) (G93A transgenic mouse) | CBE (KO of mutant SOD1)79 |
| β-thalassemia | HBB | c.93-21 G > A or c.316-197 C > T (inducing an aberrant splice) | Indels to remove a point mutation16 |
| c.126_129delCTTT (CD 41/42 (-CTTT)) | HDR (ssODN)32,33 | ||
| HDR (donor plasmid)30,34 | |||
| c.654 C > T | HDR (donor plasmid)31 | ||
| g.-28A > G | CBE80 | ||
| β-globin-related disease | HBG1 | g.-175T or g.-198Ta | ABE72,78 |
| Cancer | TP53 | c.488 A > G (p.Y163C) | CBE71 |
| Cataract | Crygc | c.461delG (at exon 3) | HDR (ssODN or w/o donor)43b |
| Cystic fibrosis | CFTR | c.1521_1523delCTT (p.F508del) | HDR (donor plasmid)50 |
| Congenital disorder of glycosylation (CDG) type-1 f | MPDU1 | c.356 T > C (p.L119P) | CBE78 |
| Chronic pain | Scn9a | c.689-1 Ca | CBE78 |
| Duchenne muscular dystrophy (DMD) | DMD | c.2983 C > T (at exon 23, p.Q995X, mdx mouse) | Large deletion using dual sgRNAs24 |
| HDR (ssODN)39,40 | |||
| HDR (Adv donor)39 | |||
| Deletion of exon 44 introducing a PTC into exon 45 | Frame-fitting indels13,14 | ||
| Indels for skipping exon 4513,14 | |||
| HDR (donor plasmid)14 | |||
| Gross deletion of exons 48-50 introducing a PTC into exon 51 | Indels to disrupt a splice acceptor at exon 51 for skipping exon 5115 | ||
| c.6913-4037 T > G (a cryptic splice acceptor at intron 47) | Indels to remove the cryptic splice acceptor15 | ||
| Gross duplication of exons 55-59 | Large deletion using dual sgRNAs15 | ||
| c.2611 C > T (p.Q871X) | ABE85 | ||
| Epidermolysis bullosa simplex (EBS) | KRT14 | c.1231 G > A (at exon 6) | HDR (donor plasmid)52 |
| Fanconi anemia | FANCF | c.828InsTAAA | HDR (ssODN)49 |
| Hemophilia A (HA) | FVIII | Gross chromosomal inversion of 140-kbp or 600-kbp involving introns 1 and 22 | Large inversion using dual sgRNAs26 |
| Gross deletion of 94,172 bp from exon 8 to intron 22 | HDR (donor plasmid)38 | ||
| Hemophilia B (HB) | FIX | c.1111 T > G (p.Y371D, mouse) | HDR (ssODN or donor plasmid)37 |
| c.1477 G > A (p.Q418G, dog) | HDR (AAV donor)35 | ||
| HDR (Adv donor)35 | |||
| c.1136 G > A (p.R379Q) (R333Q transgenic mouse) | HDR (Adv donor)36 | ||
| Hereditary tyrosinemia type I (HTI) | Fah | Insertion of a neomycin selection cassette at exon 5 (Fah∆exon5 mouse) | MMEJ-mediated KI63 |
| HMEJ-mediated KI65 | |||
| c.706 G > A (exon 8 skipping, Fah5981SB mouse) | ABE86 | ||
| Hermansky–Pudlak syndrome | HPS1 | c.1472_1487dup (16-bp duplication) | MMEJ17,19 |
| Hereditary hemochromatosis (HHC) | HFE | c.845 G > A (p.C282Y) | ABE72 |
| Limb-girdle muscular dystrophy (LGMD) | TCAP | c.26_33dup (8-bp duplication) | MMEJ17 |
| Marfan syndrome | FBN1 | c.7498 T > C | CBE82 |
| Menkes disease | ATP7A | c.6913_6917dupCTTAT | MMEJ19 |
| Myotonic dystrophy type-1 (DM1) | DMPK | CTG repeat expansion in the 3’UTR | Large deletion using dual sgRNAs22,23 |
| Phenylketonuria (PKU) | Pah | c.835 T > C (p.F263S) | CBE83 |
| Retinitis pigmentosa | Pde6b | c.1041 C > A (p.Y347X) | HDR (ssODN)47 |
| RPGR | c.1685_1686del (at exon 14) | HDR (donor plasmid)51 | |
| Mertk | Gross deletion of 1.9 kbp from intron 1 to exon 2 | NHEJ-mediated KI (HITI)59 | |
| Recessive dystrophic epidermolysis bullosa (RDEB) | COL7A1 | c.189delG (at exon 2) | HDR (IDLV donor)54 |
| c.6527insC (at exon 80) | Large deletion using dual sgRNAs25 | ||
| c.553 C > T (p.R185X) or c.1573 C > T (p.R525X) | ABE89 | ||
| Sickle cell disease (SCD) | HBB | c.20 A > T (p.E6V or p.E7V) | HDR (IDLV donor)28 |
| HDR (AAV donor)27,29 | |||
| PE96 | |||
| Tay-Sachs disease | HEXA | c.1274_1278dup | PE96 |
| Xeroderma pigmentosum, complementation group C (XPC) | XPC | c.1840C > T (p.R579X) | ABE (CRISPR-Pass)91 |
Adv adenoviral vector, IDLV integrase-defective lentiviral vector, AAV adeno-associated viral vector, PTC premature termination codon.
aInducing mutations that alleviate disease symptoms.
bUsing the normal allele on the homologous chromosome as a template.