In vivo base editing rescues ADPKD in a humanized mouse model

1. Agborbesong, E., Li, L. X., Li, L. & Li, X. Molecular mechanisms of epigenetic regulation, inflammation, and cell death in ADPKD. Front. Mol. Biosci. 9, 922428 (2022).

   Google Scholar 

2. Torres, V. E. & Harris, P. C. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 76, 149–168 (2009).

   Google Scholar 

3. Chebib, F. T. & Torres, V. E. Autosomal dominant polycystic kidney disease: core curriculum 2016. Am. J. Kidney Dis. 67, 792–810 (2016).

   Google Scholar 

4. Ecder, T. & Schrier, R. W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol. 5, 221–228 (2009).

   Google Scholar 

5. Cornec-Le Gall, E. et al. Type of PKD1 mutation influences renal outcome in ADPKD. J. Am. Soc. Nephrology: JASN 24, 1006 (2013).

   Google Scholar 

6. Zhou, J. X. et al. DNA methyltransferase 1 (DNMT1) promotes cyst growth and epigenetic age acceleration in autosomal dominant polycystic kidney disease. Kidney Int. 106, 258–272 (2024).

   Google Scholar 

7. Mao, X. et al. Cellular senescence and its association with aldose reductase promote cyst growth in autosomal dominant polycystic kidney disease. Kidney Int. 108, 811–826 (2025).

8. Levy, J. M. et al. Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses. Nat. Biomed. Eng. 4, 97–110 (2020).

   Google Scholar 

9. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

   Google Scholar 

10. Gaudelli, N. M. et al. Programmable base editing of A• T to G• C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).

    Google Scholar 

11. Koblan, L. W. et al. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice. Nature 589, 608–614 (2021).

    Google Scholar 

12. Reichart, D. et al. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nat. Med. 29, 412–421 (2023).

    Google Scholar 

13. Hopp, K. et al. Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J. Clin. Investig. 122, 4257–4273 (2012).

    Google Scholar 

14. Chen, L. et al. Engineering a precise adenine base editor with minimal bystander editing. Nat. Chem. Biol. 19, 101–110 (2023).

    Google Scholar 

15. Tan, Y. et al. Rationally engineered Staphylococcus aureus Cas9 nucleases with high genome-wide specificity. Proc. Natl Acad. Sci. 116, 20969–20976 (2019).

    Google Scholar 

16. Nishimasu, H. et al. Engineered CRISPR-Cas9 nuclease with expanded targeting space. Science 361, 1259–1262 (2018).

    Google Scholar 

17. Miller, S. M. et al. Continuous evolution of SpCas9 variants compatible with non-G PAMs. Nat. Biotechnol. 38, 471–481 (2020).

    Google Scholar 

18. Piontek, K., Menezes, L. F., Garcia-Gonzalez, M. A., Huso, D. L. & Germino, G. G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).

    Google Scholar 

19. Gainullin, V. G., Hopp, K., Ward, C. J., Hommerding, C. J. & Harris, P. C. Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner. J. Clin. Investig. 125, 607–620 (2015).

    Google Scholar 

20. Chapman, A. B. et al. Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 8, 1292–1297 (1997).

    Google Scholar 

21. Atwood, D. J. et al. Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease. Cell. Signal. 74, 109730 (2020).

    Google Scholar 

22. Ding, W. Y. et al. Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome. Sci. Transl. Med. 15, eabc8226 (2023).

    Google Scholar 

23. Furusho, T. et al. Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids. Nat. Commun. 15, 10728 (2024).

    Google Scholar 

24. Wu, G. et al. Adeno-associated virus–based gene therapy treats inflammatory kidney disease in mice. J. Clin. Investig. 134, e174722 (2024).

25. Gupta, N., Zhang, K., Sabbisetti, V., Shu, J. & Morizane, R. AAV for gene therapy drives a nephrotoxic response via NFκB in kidney organoids. Signal Transduct. Target. Ther. 10, 252 (2025).

    Google Scholar 

26. Igarashi, P. et al. Ksp-cadherin gene promoter. II. Kidney-specific activity in transgenic mice. Am. J. Physiol.-Renal Physiol. 277, F599–610 (1999).

27. Mononen, J. et al. Genetic variation is a key determinant of chromatin accessibility and drives differences in the regulatory landscape of C57BL/6J and 129S1/SvImJ mice. Nucleic Acids Res. 52, 2904–2923 (2024).

    Google Scholar 

28. Arroyo, J. et al. The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1RC/RC mouse model of autosomal dominant polycystic kidney disease. Kidney Int. 99, 1392–1407 (2021).

    Google Scholar 

29. Lala, V., Zubair, M. & Minter, D. Liver function tests. StatPearls (2023).

30. Sproston, N. R. & Ashworth, J. J. Role of C-reactive protein at sites of inflammation and infection. Front. Immunol. 9, 754 (2018).

    Google Scholar 

31. Chai, A. C. et al. Base editing correction of hypertrophic cardiomyopathy in human cardiomyocytes and humanized mice. Nat. Med. 29, 401–411 (2023).

    Google Scholar 

32. Gopalappa, R. et al. In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model. Mol. Ther. 32, 2190–2206 (2024).

    Google Scholar 

33. Swenson-Fields, K. I. et al. Macrophages promote polycystic kidney disease progression. Kidney Int 83, 855–864 (2013).

    Google Scholar 

34. Karihaloo, A. et al. Macrophages promote cyst growth in polycystic kidney disease. J. Am. Soc. Nephrology: JASN 22, 1809–1814 (2011).

    Google Scholar 

35. Chen, L. et al. Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease. J. Clin. Investig. 125, 2399–2412 (2015).

    Google Scholar 

36. Li, L. X. et al. Cross talk between lysine methyltransferase Smyd2 and TGF-β-Smad3 signaling promotes renal fibrosis in autosomal dominant polycystic kidney disease. Am. J. Physiol.-Ren. Physiol. 323, F227–F242 (2022).

    Google Scholar 

37. Zhou, J.X. et al. CD74 Promotes Cyst Growth and Renal Fibrosis in Autosomal Dominant Polycystic Kidney Disease. Cells 13 (2024).

38. Sagar, P. S. & Rangan, G. K. Cardiovascular Manifestations and Management in Autosomal Dominant Polycystic Kidney Disease. Kidney International Reports, (2023).

39. Spinelli, L., Giugliano, G. & Esposito, G. Cardiac involvement in autosomal dominant polycystic kidney disease. Cardiogenetics 11, 39–49 (2021).

    Google Scholar 

40. Xu, L. et al. Efficient precise in vivo base editing in adult dystrophic mice. Nat. Commun. 12, 3719 (2021).

    Google Scholar 

41. Jeong, Y. K., Song, B. & Bae, S. Current status and challenges of DNA base editing tools. Mol. Ther. 28, 1938–1952 (2020).

    Google Scholar 

42. Lebek, S. et al. Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease. Science 379, 179–185 (2023).

    Google Scholar 

43. Qi, M. et al. In vivo base editing of Scn5a rescues type 3 long QT syndrome in mice. Circulation 149, 317–329 (2024).

    Google Scholar 

44. Tu, T. et al. A precise and efficient adenine base editor. Mol. Ther. 30, 2933–2941 (2022).

    Google Scholar 

45. Kuo, I. Y. & Chapman, A. B. Polycystins, ADPKD, and cardiovascular disease. Kidney Int. Rep. 5, 396–406 (2020).

    Google Scholar 

46. Judge, P. K. et al. Biliary tract and liver complications in polycystic kidney disease. J. Am. Soc. Nephrol. 28, 2738–2748 (2017).

    Google Scholar 

47. Zuo, E. et al. Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science 364, 289–292 (2019).

    Google Scholar 

48. Jin, S. et al. Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice. Science 364, 292–295 (2019).

    Google Scholar 

49. Xin, H., Wan, T. & Ping, Y. Off-Targeting of Base Editors: BE3 but not ABE induces substantial off-target single nucleotide variants. Signal Transduct. Target. Ther. 4, 9 (2019).

    Google Scholar 

50. Konkalmatt, P.R. et al. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI insight 1 (2016).

51. Rubin, J. D., Nguyen, T. V., Allen, K. L., Ayasoufi, K. & Barry, M. A. Comparison of gene delivery to the kidney by adenovirus, adeno-associated virus, and lentiviral vectors after intravenous and direct kidney injections. Hum. gene Ther. 30, 1559–1571 (2019).

    Google Scholar 

52. Furusho, T. et al. Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids. bioRxiv, 2023.2007. 2028.548760 (2023).

53. Daneshgar, N. et al. Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants. Commun. Biol. 4, 1200 (2021).

    Google Scholar 

54. Schulz, M. et al. Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy. Mol. Ther. 31, 616–630 (2023).

    Google Scholar 

55. Schuster, D. J. et al. Biodistribution of adeno-associated virus serotype 9 (AAV9) vector after intrathecal and intravenous delivery in mouse. Front. Neuroanat. 8, 42 (2014).

    Google Scholar 

56. Hollidge, B. S. et al. Kinetics and durability of transgene expression after intrastriatal injection of AAV9 vectors. Front. Neurol. 13, 1051559 (2022).

    Google Scholar 

57. Muhuri, M., Levy, D. I., Schulz, M., McCarty, D. & Gao, G. Durability of transgene expression after rAAV gene therapy. Mol. Ther. 30, 1364–1380 (2022).

    Google Scholar 

58. Schindeler, A. et al. In vivo precision base editing to rescue mouse models of disease. Mol. Ther. Nucleic Acids. 36, 102622 (2025).

59. Chehelgerdi, M. et al. Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy. Mol. cancer 23, 9 (2024).

    Google Scholar 

60. Han, H. A., Pang, J. K. S. & Soh, B.-S. Mitigating off-target effects in CRISPR/Cas9-mediated in vivo gene editing. J. Mol. Med. 98, 615–632 (2020).

    Google Scholar 

61. Stone, D., Aubert, M. & Jerome, K. R. Adeno-associated virus vectors and neurotoxicity—lessons from preclinical and human studies. Gene Ther. 32, 60–73 (2025).

    Google Scholar 

62. Zarghamian, P., Klermund, J. & Cathomen, T. Clinical genome editing to treat sickle cell disease—a brief update. Front. Med. 9, 1065377 (2023).

    Google Scholar 

63. Richter, M. F. et al. Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity. Nat. Biotechnol. 38, 883–891 (2020).

    Google Scholar 

64. Zhou, X. et al. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J. Clin. Investig. 123, 3084–3098 (2013).

    Google Scholar 

65. Kottom, T. J. et al. Preclinical and Toxicology Assessment of ALW-II-41-27, an Inhibitor of the Eph Receptor A2 (EphA2). Drugs RD 24, 425–434 (2024).

    Google Scholar 

Download references