Genetic technology in the targeted therapy of Alport Syndrome
DOI:
https://doi.org/10.12775/QS.2025.38.57941Keywords
Alport, syndrome, genetic, therapy, CRISPR/Cas9, exon-skipping, premature termination codon readthrough, anti-miRNA-21 oligonucleotides, protein replacement, pharmacological chaperones, X-chromosomeAbstract
Introduction and aim of the study: Alport syndrome is the most common inherited chronic kidney disease, with three distinct patterns of inheritance: X-linked, autosomal, and digenic. Currently, there is no curative treatment for Alport syndrome. This review aims to provide updated knowledge about Alport syndrome, including its clinical and genetic characteristics and therapies that slow disease progression.
Material and Methods: A systematic literature search was conducted using PubMed and Google Scholar, with the following keywords: "gene," "therapy," "Alport," and "syndrome."
Description of the state of knowledge: Gene therapy, which uses genetic material to prevent or treat diseases, offers promising prospects for Alport syndrome. The results of the metaanalysis suggest that gene editing by CRISPR/Cas9, exon-skipping using an antisense-oligonucleotide, premature termination codon readthrough, anti-miRNA-21 oligonucleotides, protein replacement, pharmacological chaperones and X-chromosome reactivation therapies are a feasible approach for some patients with Alport syndrome.
Summary: Targeting defective collagen chains early in the disease through gene therapy may have the greatest potential to reverse this disorder. Therefore, we strongly believe Alport syndrome will become a treatable condition in the near future using gene editing techniques.
References
1. Daga S, Ding J, Deltas C, et al. The 2019 and 2021 International Workshops on Alport Syndrome [published correction appears in Eur J Hum Genet. 2024 Jan;32(1):130. https://doi.org/10.1038/s41431-023-01286-z]. Eur J Hum Genet. 2022;30(5):507-516. https://doi.org/10.1038/s41431-022-01075-0
2. THE VOICE OF THE PATIENT Externally Led Patient–Focused Drug Development
Meeting on Alport Syndrome. Submitted as patient experience data for consideration Pursuant to section 569C of the Federal Food, Drug, and Cosmetic Act to: Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA). This report reflects the National Kidney Foundation’s and Alport Syndrome Foundation’s accounts of the perspectives of patients and caregivers who participated in an Externally Led Patient-Focused Drug Development Meeting, an effort to support the FDA’s Patient-Focused Drug Development Initiative. Public Meeting: August 3, 2018. Report Date: November 1, 2019.
Accessed July 23, 2023. https://www.kidney.org/sites/default/files/vop_alport-syndrome_20191101.pdf
3. Help for children with kidney disease. Video portrait by the German Ministry of Education and Research, BMBF. Accessed July 23, 2023.
https://www.gesundheitsforschung-bmbf.de/de/videoportrait-hilfe-fur-nierenkranke-kinder-14890.php
4. Yamamura T, Horinouchi T, Nagano C, et al. Genotype-phenotype correlations influence the response to angiotensin-targeting drugs in Japanese patients with male X-linked Alport syndrome. Kidney Int. 2020;98(6):1605-1614. doi:10.1016/j.kint.2020.06.038
5. Chavez E, Rodriguez J, Drexler Y, Fornoni A. Novel Therapies for Alport Syndrome.
Front Med (Lausanne). 2022;9:848389. Published 2022 Apr 25.
https://doi.org/10.3389/fmed.2022.848389
6. Boeckhaus J, Hoefele J, Riedhammer KM, et al. Lifelong effect of therapy in young
patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study. Nephrol Dial Transplant. 2022;37(12):2496-2504. https://doi.org/10.1093/ndt/gfac006
7. Gibson JT, Huang M, Shenelli Croos Dabrera M, et al. Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome. Sci Rep. 2022;12(1):2722. Published 2022 Feb 17. doi:10.1038/s41598-022-06525-9
8. Nozu K, Nakanishi K, Abe Y, et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. Clin Exp Nephrol. 2019;23(2):158-168. doi:10.1007/s10157-018-1629-4
9. Warady BA, Agarwal R, Bangalore S, et al. Alport Syndrome Classification and Management. Kidney Med. 2020;2(5):639-649. Published 2020 Aug 7. doi:10.1016/j.xkme.2020.05.014
10. Mahrous NN, Jamous YF, Almatrafi AM, et al. A Current Landscape on Alport Syndrome Cases: Characterization, Therapy and Management Perspectives. Biomedicines. 2023;11(10):2762. Published 2023 Oct 12. doi:10.3390/biomedicines11102762
11. Namba M, Kobayashi T, Kohno M, et al. Creation of X-linked Alport syndrome rat model with Col4a5 deficiency [published correction appears in Sci Rep. 2021 Nov 8;11(1):22137. doi: 10.1038/s41598-021-01409-w]. Sci Rep. 2021;11(1):20836. Published 2021 Oct 21. doi:10.1038/s41598-021-00354-y
12. Zhao X, Shang X, Chen C, et al. Identification of four novel mutations in the COL4A5 gene identified in Chinese patients with X-linked Alport syndrome. Biomed Rep. 2020;13(2):4. doi:10.3892/br.2020.1311
13. Kamura M, Yamamura T, Omachi K, et al. Trimerization and Genotype-Phenotype Correlation of COL4A5 Mutants in Alport Syndrome. Kidney Int Rep. 2020;5(5):718-726. Published 2020 Jan 30. doi:10.1016/j.ekir.2020.01.008
14. Kashtan CE. Alport Syndrome: Achieving Early Diagnosis and Treatment. Am J Kidney Dis. 2021;77(2):272-279. doi:10.1053/j.ajkd.2020.03.026
15. Chakravarti S, Enzo E, Rocha Monteiro de Barros M, Maffezzoni MBR, Pellegrini G. Genetic Disorders of the Extracellular Matrix: From Cell and Gene Therapy to Future Applications in Regenerative Medicine. Annu Rev Genomics Hum Genet. 2022;23:193-222. doi:10.1146/annurev-genom-083117-021702
16. Boeckhaus J, Hoefele J, Riedhammer KM, et al. Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial. Clin Genet. 2021;99(1):143-156. doi:10.1111/cge.13861
17. Hadjipanagi D, Papagregoriou G, Koutsofti C, et al. Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece. Genes (Basel). 2022;13(12):2203. Published 2022 Nov 24. doi:10.3390/genes13122203
18. KDIGO Conference Participants. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2022;101(6):1126-1141. doi:10.1016/j.kint.2022.03.019
19. Gomes AM, Lopes D, Almeida C, et al. Potential Renal Damage Biomarkers in Alport Syndrome-A Review of the Literature. Int J Mol Sci. 2022;23(13):7276. Published 2022 Jun 30. doi:10.3390/ijms23137276
20. Oda Y, Sawa N, Nozu K, Ubara Y. Refractory focal segmental glomerulosclerosis caused by Alport syndrome detected by genetic testing after three decades. BMJ Case Rep. 2022;15(3):e247393. Published 2022 Mar 14. doi:10.1136/bcr-2021-247393
21. Kashtan CE, Ding J, Garosi G, et al. Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int. 2018;93(5):1045-1051. doi:10.1016/j.kint.2017.12.018
22. Yamamura T, Nozu K, Fu XJ, et al. Natural History and Genotype-Phenotype Correlation in Female X-Linked Alport Syndrome. Kidney Int Rep. 2017;2(5):850-855. Published 2017 May 4. doi:10.1016/j.ekir.2017.04.011
23. Kashtan CE, Ding J, Gregory M, et al. Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol. 2013;28(1):5-11. doi:10.1007/s00467-012-2138-4
24. Mabillard H, Sayer JA. SGLT2 inhibitors - a potential treatment for Alport syndrome. Clin Sci (Lond). 2020;134(4):379-388. doi:10.1042/CS20191276
25. Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med. 1996;2(4):467-469. doi:10.1038/nm0496-467
26. Boels MG, Avramut MC, Koudijs A, et al. Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy. Diabetes. 2016;65(8):2429-2439. doi:10.2337/db15-1413
27. Pedigo CE, Ducasa GM, Leclercq F, et al. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J Clin Invest. 2016;126(9):3336-3350. doi:10.1172/JCI85939
28. Sun L, Kuang XY, Zhang J, Huang WY. Hydroxychloroquine Ameliorates Hematuria in Children with X-Linked Alport Syndrome: Retrospective Case Series Study. Pharmgenomics Pers Med. 2023;16:145-151. Published 2023 Feb 25. doi:10.2147/PGPM.S394290
29. Guo J, Song W, Boulanger J, et al. Dysregulated Expression of microRNA-21 and Disease-Related Genes in Human Patients and in a Mouse Model of Alport Syndrome. Hum Gene Ther. 2019;30(7):865-881. doi:10.1089/hum.2018.205
30. Chertow GM, Appel GB, Andreoli S, et al. Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome. Am J Nephrol. 2021;52(3):180-189. doi:10.1159/000513777
31. Kumar SR, Markusic DM, Biswas M, High KA, Herzog RW. Clinical development of gene therapy: results and lessons from recent successes. Mol Ther Methods Clin Dev. 2016;3:16034. Published 2016 May 25. doi:10.1038/mtm.2016.34
32. Hawsawi YM, Shams A, Theyab A, et al. The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19. Front Cell Infect Microbiol. 2022;12:869889. Published 2022 Jun 9. doi:10.3389/fcimb.2022.869889
33. Cox DB, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med. 2015;21(2):121-131. doi:10.1038/nm.3793 34. Quinlan C, Rheault MN. Genetic Basis of Type IV Collagen Disorders of the Kidney. Clin J Am Soc Nephrol. 2021;16(7):1101-1109. doi:10.2215/CJN.19171220
35. Zhao Y, Zheng Q, Xie J. Exploration of Gene Therapy for Alport Syndrome. Biomedicines. 2024;12(6):1159. Published 2024 May 23. doi:10.3390/biomedicines12061159
36. Karginov FV, Hannon GJ. The CRISPR system: small RNA-guided defense in bacteria and archaea. Mol Cell. 2010;37(1):7-19. doi:10.1016/j.molcel.2009.12.033
37. Casini A, Olivieri M, Petris G, et al. A highly specific SpCas9 variant is identified by in vivo screening in yeast. Nat Biotechnol. 2018;36(3):265-271. doi:10.1038/nbt.4066
38. Lee J, Jung MH, Jeong E, Lee JK. Using Sniper-Cas9 to Minimize Off-target Effects of CRISPR-Cas9 Without the Loss of On-target Activity Via Directed Evolution. J Vis Exp. 2019;(144):10.3791/59202. Published 2019 Feb 26. doi:10.3791/59202
39. WareJoncas Z, Campbell JM, Martínez-Gálvez G, et al. Precision gene editing technology and applications in nephrology. Nat Rev Nephrol. 2018;14(11):663-677. doi:10.1038/s41581-018-0047-x
40. Daga S, Donati F, Capitani K, et al. New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells [published correction appears in Eur J Hum Genet. 2024 Jan;32(1):131. doi: 10.1038/s41431-023-01287-y]. Eur J Hum Genet. 2020;28(4):480-490. doi:10.1038/s41431-019-0537-8
41. Omachi K, Miner JF. Comparative analysis and rational design of dCas9-VP64
variants for CRISPR activation. bioRxiv. 2021. https://doi.org/10.1101/ 2021.08.13.456279.
42. Lin X, Suh JH, Go G, Miner JH. Feasibility of repairing glomerular basement membrane defects in Alport syndrome. J Am Soc Nephrol. 2014;25(4):687-692. doi:10.1681/ASN.2013070798
43. Funk SD, Bayer RH, Miner JH. Endothelial cell-specific collagen type IV-α3 expression does not rescue Alport syndrome in Col4a3-/- mice. Am J Physiol Renal Physiol. 2019;316(5):F830-F837. doi:10.1152/ajprenal.00556.2018
44. Yamamura T, Horinouchi T, Adachi T, et al. Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. Nat Commun. 2020;11(1):2777. Published 2020 Jun 2. doi:10.1038/s41467-020-16605-x
45. Yabuuchi K, Horinouchi T, Yamamura T, Nozu K, Takasato M. Investigation of exon skipping therapy in kidney organoids from Alport syndrome patients derived iPSCs. Genes Cells. 2024;29(12):1118-1130. doi:10.1111/gtc.13170
46. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203-222. doi:10.1038/nrd.2016.246
47. Gomez IG, MacKenna DA, Johnson BG, et al. Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest. 2015;125(1):141-156. doi:10.1172/JCI75852
48. Rubel D, Boulanger J, Craciun F, et al. Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models. Cells. 2022;11(4):594. Published 2022 Feb 9. doi:10.3390/cells11040594
49. Lin MH, Miller JB, Kikkawa Y, Suleiman HY, Tryggvason K, Hodges BL, Miner JH. Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome. J Am Soc Nephrol. 2018 May;29(5):1426-1436. doi: 10.1681/ASN.2017060690. Epub 2018 Feb 22. PMID: 29472414; PMCID: PMC5967757.
50. Boudko SP, Bauer R, Chetyrkin SV, Ivanov S, Smith J, Voziyan PA, Hudson BG. Collagen IVα345 dysfunction in glomerular basement membrane diseases. II. Crystal structure of the α345 hexamer. J Biol Chem. 2021 Jan-Jun;296:100591. doi: 10.1016/j.jbc.2021.100591. Epub 2021 Mar 26. PMID: 33775698; PMCID: PMC8093946.
51. Pedchenko V, Boudko SP, Barber M, Mikhailova T, Saus J, Harmange JC, Hudson BG. Collagen IVα345 dysfunction in glomerular basement membrane diseases. III. A functional framework for α345 hexamer assembly. J Biol Chem. 2021 Jan-Jun;296:100592. doi: 10.1016/j.jbc.2021.100592. Epub 2021 Mar 26. PMID: 33775696; PMCID: PMC8099640
52. Tran ML, Génisson Y, Ballereau S, Dehoux C. Second-Generation Pharmacological Chaperones: Beyond Inhibitors. Molecules. 2020 Jul 9;25(14):3145. doi: 10.3390/molecules25143145. PMID: 32660097; PMCID: PMC7397201.
53. Petropoulos S, Edsgärd D, Reinius B, et al. Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos [published correction appears in Cell. 2016 Sep 22;167(1):285. doi: 10.1016/j.cell.2016.08.009]. Cell. 2016;165(4):1012-1026. doi:10.1016/j.cell.2016.03.023
54. Li X, Le Y, Zhang Z, Nian X, Liu B, Yang X. Viral Vector-Based Gene Therapy. Int J Mol Sci. 2023;24(9):7736. Published 2023 Apr 23. doi:10.3390/ijms24097736
55. Peek JL, Wilson MH. Cell and gene therapy for kidney disease. Nat Rev Nephrol. 2023;19(7):451-462. doi:10.1038/s41581-023-00702-3 56. Ding WY, Kuzmuk V, Hunter S, et al. Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome. Sci Transl Med. 2023;15(708):eabc8226. doi:10.1126/scitranslmed.abc8226
57. Riedmayr LM, Hinrichsmeyer KS, Thalhammer SB, et al. mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy. Nat Commun. 2023;14(1):6578. Published 2023 Oct 18. doi:10.1038/s41467-023-42386-0
58. Tang H, Wang H, Wang S, et al. Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin. Hum Genet. 2023;142(2):289-304. doi:10.1007/s00439-022-02504-2
59. Qi J, Tan F, Zhang L, et al. AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness. Adv Sci (Weinh). 2024;11(11):e2306788. doi:10.1002/advs.202306788
60. Lv J, Wang H, Cheng X, et al. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial [published correction appears in Lancet. 2024 May 25;403(10441):2292. doi: 10.1016/S0140-6736(24)01040-7]. Lancet. 2024;403(10441):2317-2325. doi:10.1016/S0140-6736(23)02874-X
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Magdalena Kłusek, Bartosz Pawłowski, Michał Sienkiewicz, Anna Mandziuk
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 293
Number of citations: 0
