Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies
Abstract
:1. Introduction
1.1. Genetic Kidney Diseases
1.1.1. Autosomal Dominant Polycystic Kidney Disease (ADPKD)
1.1.2. Autosomal Recessive Polycystic Kidney Disease (ARPKD)
1.1.3. Alport Syndrome (AS)
1.1.4. Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)
1.1.5. Gitelman (GS) and Bartter (BS) Syndromes
1.2. Site-Specific Nuclease Systems
1.2.1. Zinc Finger Nucleases (ZFNs)
1.2.2. Transcription Activator-Like Effector Nucleases (TALENs)
1.2.3. Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR Associated Protein 9 Nuclease (CRISPR-Cas9)
1.2.4. Comparison of the Three Types of Genome Editing Technologies
Sequence Selection and Assembly Evaluation
Delivery Strategies
Specificity and Efficiency
2. Site-Specific Nuclease Systems to Study Genetic Kidney Diseases
2.1. ADPKD Models Generated Using Genome Editing
2.1.1. ADPKD Models Generated Using ZFNs
2.1.2. ADPKD Models Generated Using TALENs
2.1.3. ADPKD Models Generated Using CRISPR-Cas9
2.2. ARPKD Models Generated Using Genome Editing
ARPKD Models Generated Using CRISPR-Cas9
2.3. AS Models Generated Using Genome Editing
AS Models Generated Using CRISPR-Cas9
2.4. ADTKD Models Generated Using Genome Editing
2.4.1. ADTKD Models Generated Using ZFNs
2.4.2. ADTKD Models Generated Using CRISPR-Cas9
2.5. GS and BS Models Generated Using Genome Editing
2.5.1. BS Models Generated Using ZFNs
2.5.2. BS Models Generated Using TALENs
3. Main Challenges to Overcome
3.1. Difficulty of Gene Delivery to the Kidney
3.2. Immune System against Gene Editing
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Disease | Estimated Incidende (per 100,000 Population) | Gene | Protein | Function |
---|---|---|---|---|
Autosomal dominant polycystic kidney disease (CL) | ~100 individuals | PKD1 PKD2 GANAβ DNAJB11 IFT140 | Polycystin-1 Polycystin-2 Glucosidase II subunit α DnaJ homolog subfamily B member 11 Intraflagellar transport protein 140 homolog | Calcium ion transmembrane transport Calcium ion transmembrane transport Alpha-glucosidase activity Misfolded protein binding Cilium assembly |
Autosomal recessive polycystic kidney disease (CL) | ~5 individuals | PKHD1 DZIP1L | Polyductin Cilium assembly protein DZIP1L | Cell-cell adhesion Metal ion binding |
Alport syndrome (GL) | ~50 individuals | COL4A3 COL4A4 COL4A5 | Collagen alpha-3 (IV) chain Collagen alpha-4 (IV) chain Collagen alpha-5 (IV) chain | Extracellular matrix organization |
Autosomal dominant tubulointerstitial kidney disease (TL) | N/A | UMOD MUC1 REN HNF1B SEC61A1 | Uromodulin Mucin-1 Renin Hepatocyte nuclear factor 1β α1 subunit of the SEC61 | Cellular defense response DNA damage response Cell maturation Transcription factor Endoplasmatic reticulum organization |
Gitelman syndrome (TL) | ~2 individuals | SLC12A3 | Solute carrier family 12 member 3 | Ion transport |
Bartter syndrome (TL) | <1 individual | SLC12A1 KCNJ1 CLCNKA CLCNKB BSND MAGED2 | Solute carrier family 12 member 1 ATP-sensitive inward rectifier potassium channel 1 Chloride channel protein ClC-Ka Chloride channel protein ClC-Kb Barttin Melanoma-associated antigen D2 | Ion transport Potassium ion transport Chloride transport Chloride transport Chloride transport Sodium ion absorption |
ZFNs | TALENs | CRISPR-Cas9 | References | |
---|---|---|---|---|
Recognition site | Zinc finger motif | RVD region of tandem TALE repeat | Single-strand guide RNA | [72,77,80] |
Endonuclease | FokI nuclease | FokI nuclease | Cas9 nuclease | [72,77,80] |
Target sequence size | 9–18 bp per ZFP monomer | 14–20 bp per TALE monomer | 20 bp guide sequence | [71,79,83] |
Targeting limitations | Difficult to target non-G-rich sites | 5ʹ targeted base must be a T for each TALEN monomer | Targeted site must precede a PAM sequence | [69,86,87] |
Delivery (in vivo) | AAVs, LVs, AdVs | LVs, AdVs | AAVs, LVs | [69,88] |
Specificity | Tolerating a small number of positional mismatches | Tolerating a small number of positional mismatches | Tolerating multiple consecutive mismatches | [89] |
Efficiency | ~12% | ~76% | ~81% | [69,90] |
Cost (Single experiment) | $5000 | $500 | $30 | [91] |
Overall evaluation | Good | Very good | Excellent |
Gene | Tool | Model | Key Finding | Refs. |
---|---|---|---|---|
Autosomal dominant polycystic kidney disease | ||||
PKD1 | ZFN | Mini pig | Heterozygous PKD1 mini pigs develop cysts. | [119] |
TALEN and CRISPR | MDCK and mIMCD3 | Protocol for creating knockout cell lines | [120] | |
CRISPR | Kidney organoids | Knockout of PKD1 causes cysts | [121] | |
CRISPR | Kidney organoids | Growing kidney organoids in suspension culture enhances cystogenesis | [122] | |
CRISPR | UB organoids | cAMP signaling is involved in cystogenesis | [123] | |
CRISPR | Kidney organoids | By using knockout pools it is possible to generate cystogenesis | [124] | |
CRISPR | Monkey | Heterozygous PKD1 monkeys show cystogenesis perinatally | [125] | |
CRISPR | Pig | Heterozygous PKD1 pigs develop many pathological conditions similar to ADPKD patients | [126] | |
PKD2 | TALEN | MDCK and mIMCD3 | Protocol to creation knockout cell lines | [120] |
CRISPR | Kidney organoids | Knockout of PKD2 causes cysts | [121] | |
CRISPR | Kidney organoids | Growing organoids in suspension culture enhances cystogenesis | [122] | |
CRISPR | Kidney organoids | By using knockout pools it is possible to generate cystogenesis | [124] | |
CRISPR | HEK-293 | Knockout of PKD2 does not alter energy metabolism | [127] | |
Pde1a | TALEN | Mouse | Knockout of Pde1a aggravates cystogenesis | [128] |
TALEN | Mouse | Knockout of Pde1a aggravates cystogenesis | [129] | |
GANAβ | CRISPR | RCTE | Knockout of GANAβ causes PC1 and PC2 maturation and localization defects | [14] |
Autosomal recessive polycystic kidney disease | ||||
PKHD1 | CRISPR | HEK-293 | Knockout of PKHD1 alters energy metabolism | [127] |
CRISPR | Kidney organoids | CRISPR-knockin as a method to correct pathogenic variants. | [130] | |
CRISPR | Mouse | Heterozygous Pkhd1 develop proximal tubule ectasia | [131] | |
dzip1l | CRISPR | Zebrafish | DZIP1L is involved in the formation of primary cilia | [28] |
P2rx7 | CRISPR | Mouse | P2X7 contributes to cyst growth by increasing pannexin-1-dependent ATP release into the lumen | [132] |
Alport Syndrome | ||||
COL4A3 | CRISPR | Mouse podocytes | Knockout of Col4a causes endoplasmic reticulum stress and apoptosis | [133] |
CRISPR | Human podocytes | Innovative protocol for COL4A3 correction by HDR | [134] | |
COL4A5 | CRISPR | Human podocytes | Innovative protocol for COL4A5 correction by HDR | [134] |
CRISPR | Human podocytes | CRISPR-knockin as a method for confirming the pathogenicity of missense variants | [135] | |
CRISPR | Mouse | Heterozygous Col4a5 male mice develop many pathological conditions similar to AS patients | [136] | |
Lamb2 | CRISPR | Mouse | Heterozygous mutations in a gene encoding GBM components aggravate AS phenotype | [137] |
Autosomal dominant tubulointerstitial kidney disease | ||||
Ren | ZFN | SS rat | Knockout of Ren causes poor renal function | [138] |
HNF1B | CRISPR | Kidney organoids | Knockout of HNF1B prevents proper formation of certain components of the nephron | [139] |
sec61al2 | CRISPR | Zebrafish | Mutations in sec61al2 causes pronephric tubules defects | [55] |
Umod | CRISPR | Mouse | Heterozygous Umod mice develop many pathological conditions similar to ADTKD-UMOD patient | [140] |
Gitelman and Bartter syndromes | ||||
Kcnj1 | ZFN | SS rat | Knockout of Kcnj1 protects against salt-induced hypertension and renal injury | [141] |
Clcnk2 | TALEN | Mouse | ClC-K2-deficient mice develop many pathological conditions similar to BS patient | [142] |
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Gómez-García, F.; Martínez-Pulleiro, R.; Carrera, N.; Allegue, C.; Garcia-Gonzalez, M.A. Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies. Cells 2022, 11, 1571. https://doi.org/10.3390/cells11091571
Gómez-García F, Martínez-Pulleiro R, Carrera N, Allegue C, Garcia-Gonzalez MA. Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies. Cells. 2022; 11(9):1571. https://doi.org/10.3390/cells11091571
Chicago/Turabian StyleGómez-García, Fernando, Raquel Martínez-Pulleiro, Noa Carrera, Catarina Allegue, and Miguel A. Garcia-Gonzalez. 2022. "Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies" Cells 11, no. 9: 1571. https://doi.org/10.3390/cells11091571
APA StyleGómez-García, F., Martínez-Pulleiro, R., Carrera, N., Allegue, C., & Garcia-Gonzalez, M. A. (2022). Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies. Cells, 11(9), 1571. https://doi.org/10.3390/cells11091571