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Progress with RNA Interference for the Treatment of Primary Hyperoxaluria

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Abstract

Over the last few years, US Food and Drug Administration-approved drugs using RNA interference have come to the market. Many have treated liver-specific diseases utilizing N-acetyl galactosamine conjugation because of its effective delivery and limited off-target effects. The autosomal recessive disorder primary hyperoxaluria, specifically type 1, has benefited from these developments. Primary hyperoxaluria arises from mutations in the enzymes involved in endogenous oxalate synthesis. The severity of disease varies but can result in kidney failure and systemic oxalosis. Until recently, the treatment options were limited and focused primarily on supportive treatments, pyridoxine use in a subset of patients with primary hyperoxaluria type 1, and liver-kidney transplants in those who progressed to kidney failure. Two genes have been targeted with RNA interference; lumasiran targets glycolate oxidase and nedosiran targets lactate dehydrogenase A. Lumasiran was recently approved in the treatment of primary hyperoxaluria type 1 and nedosiran is in the approval process. Unfortunately, despite initial hopes that nedosiran may also be a treatment option for primary hyperoxaluria types 2 and 3, initial data suggest otherwise. The use of RNA interference liver-specific targeting for the treatment of primary hyperoxaluria type 1 will likely transform the natural history of the disease.

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References

  1. Holmes RP, Assimos DG. Glyoxylate synthesis, and its modulation and influence on oxalate synthesis. J Urol. 1998;160(5):1617–24.

    Article  CAS  Google Scholar 

  2. Burns Z, Knight J, Fargue S, et al. Future treatments for hyperoxaluria. Curr Opin Urol. 2020;30(2):171–6.

    Article  Google Scholar 

  3. Liebow A, Li X, Racie T, et al. An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. J Am Soc Nephrol. 2017;28:494–503.

    Article  CAS  Google Scholar 

  4. Lai C, Pursell N, Gierut J, et al. Specific inhibition of hepatic lactate dehydrogenase reduces oxalate production in mouse models of primary hyperoxaluria. Mol Ther. 2018;26(8):1983–95.

    Article  CAS  Google Scholar 

  5. Wood KD, Holmes RP, Erbe D, et al. Reduction in urinary oxalate excretion in mouse models of primary hyperoxaluria by RNA interference inhibition of liver lactate dehydrogenase activity. Biochim Biophys Acta Mol Basis Dis. 2019;1865(9):2203–9.

    Article  CAS  Google Scholar 

  6. Frishberg Y, Zeharia A, Lyakhovetsky R, Bargal R, Belostotsky R. Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria. J Med Genet. 2014;51(8):526–9. https://doi.org/10.1136/jmedgenet-2014-102529.

    Article  CAS  PubMed  Google Scholar 

  7. McGregor TL, Hunt KA, Yee E, et al. Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria. Elife. 2020;9:e54363.

    Article  CAS  Google Scholar 

  8. Kanno T, Sudo K, Takeuchi I, et al. Hereditary deficiency of lactate dehydrogenase M-subunit. Clin Chim Acta. 1980;108(2):267–76.

    Article  CAS  Google Scholar 

  9. Nishimura Y, Honda N, Ohyama K, et al. Lactate dehydrogenase A subunit deficiency. Isozymes Curr Top Biol Med Res. 1983;11:51–64.

    CAS  PubMed  Google Scholar 

  10. Maekawa M, Kanda S, Sudo K, et al. Estimation of the gene frequency of lactate dehydrogenase subunit deficiencies. Am J Hum Genet. 1984;36(6):1204–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kanno T, Sudo K, Maekawa M, et al. Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy. Clin Chim Acta. 1988;173(1):89–98.

    Article  CAS  Google Scholar 

  12. Maekawa M, Kanno T, Sudo K. Myoglobinuria due to enzyme abnormalities in glycolytic pathway: especially lactate dehydrogenase M subunit deficiency. Rinsho Byori. 1991;39(2):124–32.

    CAS  PubMed  Google Scholar 

  13. Ariceta G, Barrios K, Brown BD, Hoppe B, Rosskamp R, Langman CB. Hepatic lactate dehydrogenase A: an RNA interference target for the treatment of all known types of primary hyperoxaluria. Kidney Int Rep. 2021;6:1088–98.

    Article  Google Scholar 

  14. Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med. 2021;384:1216–26.

    Article  CAS  Google Scholar 

  15. Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013;369(7):649–58.

    Article  CAS  Google Scholar 

  16. Salido E, Pey AL, Rodriguez R, et al. Primary hyperoxalurias: disorders of glyoxylate detoxification. Biochim Biophys Acta. 2012;1822(9):1453–64.

    Article  CAS  Google Scholar 

  17. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290–6. https://doi.org/10.1159/000086360.

    Article  PubMed  Google Scholar 

  18. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 2012;8(8):467–75. https://doi.org/10.1038/nrneph.2012.113.

    Article  CAS  PubMed  Google Scholar 

  19. Cochat P, Hulton SA, Acquaviva C, et al. Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant. 2012;27(5):1729–36. https://doi.org/10.1093/ndt/gfs078.

    Article  CAS  PubMed  Google Scholar 

  20. Bergstralh EJ, Monico CG, Lieske JC, et al. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493–501. https://doi.org/10.1111/j.1600-6143.2010.03271.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cramer SD, Ferree PM, Lin K, et al. The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet. 1999;11:2063–9.

    Article  Google Scholar 

  22. Monico CG, Rossetti S, Belostotsky R, et al. Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol. 2011;6(9):2289–95.

    Article  CAS  Google Scholar 

  23. Belostotsky R, Seboun E, Idelson GH, et al. Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet. 2010;87:392–9.

    Article  CAS  Google Scholar 

  24. Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806–11.

    Article  CAS  Google Scholar 

  25. Hannon GJ. RNA interference. Nature. 2002;418(6894):244–51.

    Article  CAS  Google Scholar 

  26. Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136(49):16958–61.

    Article  CAS  Google Scholar 

  27. Wu YT, Jiaang WT, Lin KG, et al. A new N-acetylgalactosamine containing peptide as a targeting vehicle for mammalian hepatocytes via asialoglycoprotein receptor endocytosis. Curr Drug Deliv. 2004;1(2):119–27.

    Article  CAS  Google Scholar 

  28. Bobbin ML, Rossi JJ. RNA interference (RNAi)-based therapeutics: delivering on the promise? Annu Rev Pharmacol Toxicol. 2016;56:103–22. https://doi.org/10.1146/annurev-pharmtox-010715-103633.

    Article  CAS  PubMed  Google Scholar 

  29. Scott LJ, Keam SJ. Lumasiran: first approval. Drugs. 2021;81:277–82.

    Article  CAS  Google Scholar 

  30. Frishberg Y, Deschênes G, Groothoff JW, et al. Phase 1/2 study of lumasiran for treatment of primary hyperoxaluria type 1: a placebo-controlled randomized clinical trial. Clin J Am Soc Nephrol. 2021;16:1025–36.

    Article  CAS  Google Scholar 

  31. Sas DJ, Magen D, Hayes W, et al. Phase 3 trial of lumasiran for primary hyperoxaluria type 1: a new RNAi therapeutic in infants and young children. Genet Med. 2022;24(3):654–62.

    Article  Google Scholar 

  32. Dicerna Pharmaceuticals, Inc. Dicerna reports positive top-line results from PHYOX™2 pivotal clinical trial of nedosiran for the treatment of primary hyperoxaluria. 2021. https://investors.dicerna.com/news-releases/news-release-details/dicerna-reports-positive-top-line-results-phyoxtm2-pivotal. Accessed 15 Mar 2022.

  33. Hoppe B, Koch A, Cochat P, et al. Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHOX1) in primary hyperoxaluria. Kidney Int. 2022;101(3):626–34.

    Article  CAS  Google Scholar 

  34. Dicerna Pharmaceuticals, Inc. Dicerna announces results for PHYOX™4, single-dose study of nedosiran in primary hyperoxaluria type 3 (PH3). 2021. https://www.businesswire.com/news/home/20211019005355/en/. Accessed 15 Mar 2022.

  35. Hulton SA, Groothoff JW, Frishberg Y, et al. Randomized clinical Trial on the long-term efficacy and safety of lumasiran in patients with primary hyperoxaluria type 1. Kidney Int Rep. 2021;7(3):494–506. https://doi.org/10.1016/j.ekir.2021.12.001.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Marnix E. Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Kathryn Sawyer & Stephen Leahy

  2. Department of Urology, University of Alabama at Birmingham, 1720 2nd Ave South, Birmingham, AL, 35294, USA

    Kyle D. Wood

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Correspondence to Kyle D. Wood.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Kyle Wood reports consulting fees and is on the scientific advisory board for Alnylam Pharmaceuticals. All other authors report no potential conflicts of interest or financial disclosures that are pertinent to the article.

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All authors contributed to the literature review, writing, and editing of the article.

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Sawyer, K., Leahy, S. & Wood, K.D. Progress with RNA Interference for the Treatment of Primary Hyperoxaluria. BioDrugs 36, 437–441 (2022). https://doi.org/10.1007/s40259-022-00539-5

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