Skip to main content
SpringerLink
Log in

Molecular therapy of primary hyperoxaluria

  • SSIEM 2016
  • Published:
Journal of Inherited Metabolic Disease

Abstract

During the last few decades, the molecular understanding of the mechanisms involved in primary hyperoxalurias (PHs) has set the stage for novel therapeutic approaches. The availability of PH mouse models has facilitated preclinical studies testing innovative treatments. PHs are autosomal recessive diseases where the enzymatic deficit plays a central pathogenic role. Thus, molecular therapies aimed at restoring such deficit or limiting the consequences of the metabolic derangement could be envisioned, keeping in mind the specific challenges posed by the cell-autonomous nature of the deficiency. Various molecular approaches like enzyme replacement, substrate reduction, pharmacologic chaperones, and gene and cell therapies have been explored in cells and mouse models of disease. Some of these proof-of-concept studies have paved the way to current clinical trials on PH type 1, raising hopes that much needed treatments will become available for this severe inborn error of metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A (1996) Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 155:839–843

    Article  CAS  PubMed  Google Scholar 

  • Bourhis JM, Vignaud C, Pietrancosta N et al (2009) Structure of human glycolate oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1,2,3-thiadiazole. Acta Crystallogr Sect F Struct Biol Cryst Commun 65:1246–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casanueva MO, Burga A, Lehner B (2012) Fitness trade-offs and environmentally induced mutation buffering in isogenic C. elegans. Science 335:82–85

    Article  CAS  PubMed  Google Scholar 

  • Castello R, Borzone R, D’Aria S, Annunziata P, Piccolo P, Brunetti-Pierri N (2016) Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther 23:129–134

    Article  CAS  PubMed  Google Scholar 

  • Cellini B, Montioli R, Paiardini A, Lorenzetto A, Voltattorni CB (2009) Molecular insight into the synergism between the minor allele of human liver Peroxisomal alanine:Glyoxylate aminotransferase and the F152I mutation. J Biol Chem 284:8349–8358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cibrik DM, Kaplan B, Arndorfer JA, Meier-Kriesche H-U (2002) Renal allograft survival in patients with oxalosis. Transplantation 74:707–710

    Article  CAS  PubMed  Google Scholar 

  • Cochat P, Hulton S-A, Acquaviva C et al (2012) Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant 27:1729–1736

    Article  CAS  PubMed  Google Scholar 

  • Cochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 369:649–658

    Article  CAS  PubMed  Google Scholar 

  • Chung J, Granja I, Taylor MG, Mpourmpakis G, Asplin JR, Rimer JD (2016) Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature 536:446–450

    Article  CAS  PubMed  Google Scholar 

  • D’Avola D, López-Franco E, Sangro B et al (2016) Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol 65:776–783

    Article  PubMed  Google Scholar 

  • Danpure CJ (2006) Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways. Biochim Biophys Acta 1763:1776–1784

    Article  CAS  PubMed  Google Scholar 

  • Danpure CJ, Jennings PR, Fryer P, Purdue PE, Allsop J (1994) Primary hyperoxaluria type 1: genotypic and phenotypic heterogeneity. J Inherit Metab Dis 17:487–499

    Article  CAS  PubMed  Google Scholar 

  • Danpure CJ, Purdue PE, Fryer P et al (1993) Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet 53:417–432

    CAS  PubMed  PubMed Central  Google Scholar 

  • Danpure CJ, Rumsby G (2004) Molecular aetiology of primary hyperoxaluria and its implications for clinical management. Expert Rev Mol Med 6:1–16

    Article  PubMed  Google Scholar 

  • Dutta C, Avitahl-Curtis N, Pursell N et al (2016) Inhibition of Glycolate oxidase with dicer-substrate siRNA reduces calcium oxalate deposition in a mouse model of primary hyperoxaluria type 1. Mol Ther 24:770–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fargue S, Knight J, Holmes RP, Rumsby G, Danpure CJ (2016) Effects of alanine: glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay. Biochim Biophys Acta 1862:1055–1062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fargue S, Lewin J, Rumsby G, Danpure CJ (2013) Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele. J Biol Chem 288:2475–2484

    Article  CAS  PubMed  Google Scholar 

  • Frishberg Y, Zeharia A, Lyakhovetsky R, Bargal R, Belostotsky R (2014) Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria. J Med Genet 51:526–529

    Article  CAS  PubMed  Google Scholar 

  • George LA, Fogarty PF (2016) Gene therapy for hemophilia: past, present and future. Semin Hematol 53:46–54

    Article  CAS  PubMed  Google Scholar 

  • Gibbs DA, Watts RW (1970) The action of pyridoxine in primary hyperoxaluria. Clin Sci 38:277–286

    Article  CAS  PubMed  Google Scholar 

  • Goldstein SL, Jaber BL, Faubel S, Chawla LS, Acute Kidney Injury Advisory Group of American Society of Nephrology (2013) AKI transition of care: a potential opportunity to detect and prevent CKD. Clin J Am Soc Nephrol 8:476–483

    Article  CAS  PubMed  Google Scholar 

  • Guha C, Yamanouchi K, Jiang J et al (2005) Feasibility of hepatocyte transplantation-based therapies for primary hyperoxalurias. Am J Nephrol 25:161–170

    Article  PubMed  Google Scholar 

  • Harambat J, Fargue S, Bacchetta J, Acquaviva C, Cochat P (2011) Primary hyperoxaluria. Int J Nephrol 2011:864580

    Article  PubMed  PubMed Central  Google Scholar 

  • Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol 16:574–581

    Article  CAS  PubMed  Google Scholar 

  • Hirsch ML, Green L, Porteus MH, Samulski RJ (2010) Self-complementary AAV mediates gene targeting and enhances endonuclease delivery for double-strand break repair. Gene Ther 17:1175–1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmes RP, Assimos DG (1998) Glyoxylate synthesis, and its modulation and influence on oxalate synthesis. J Urol 160:1617–1624

    Article  CAS  PubMed  Google Scholar 

  • Hopp K, Cogal AG, Bergstralh EJ et al (2015) Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 26:2559–2570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoppe B, Beck BB, Milliner DS (2009) The primary hyperoxalurias. Kidney Int 75:1264–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoppe B, Leumann E, von Unruh G, Laube N, Hesse A (2003) Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria. Front Biosci 8:e437–e443

    Article  CAS  PubMed  Google Scholar 

  • Hoppe B, Niaudet P, Salomon R et al (2016) A randomised phase I/II trial to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Pediatr Nephrol. doi:10.1007/s00467-016-3553-8

    Google Scholar 

  • Hopper ED, Pittman AMC, Fitzgerald MC, Tucker CL (2008) In vivo and in vitro examination of stability of primary hyperoxaluria-associated human alanine:glyoxylate aminotransferase. J Biol Chem 283:30493–30502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamieson NV, European PHI Transplantation Study Group (2005) A 20-year experience of combined liver/kidney transplantation for primary hyperoxaluria (PH1): the European PH1 transplant registry experience 1984-2004. Am J Nephrol 25:282–289

    Article  PubMed  Google Scholar 

  • Jiang J, Salido EC, Guha C et al (2008) Correction of hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type-1. Transplantation 85:1253–1260

    Article  CAS  PubMed  Google Scholar 

  • Jones JM, Morrell JC, Gould SJ (2000) Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases. J Biol Chem 275:12590–12597

    Article  CAS  PubMed  Google Scholar 

  • Kivelä JM, Räisänen-Sokolowski A, Pakarinen MP et al (2011) Long-term renal function in children after liver transplantation. Transplantation 91:115–120

    Article  PubMed  Google Scholar 

  • Knight J, Jiang J, Assimos DG, Holmes RP (2006) Hydroxyproline ingestion and urinary oxalate and glycolate excretion. Kidney Int 70:1929–1934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leumann E, Hoppe B (2001) The primary hyperoxalurias. J Am Soc Nephrol 12:1986–1993

    CAS  PubMed  Google Scholar 

  • Louis Jeune V, Joergensen JA, Hajjar RJ, Weber T (2013) Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods 24:59–67

    Article  CAS  PubMed  Google Scholar 

  • Luheshi LM, Dobson CM (2009) Bridging the gap: from protein misfolding to protein misfolding diseases. FEBS Lett 583:2581–2586

    Article  CAS  PubMed  Google Scholar 

  • Lumb MJ, Danpure CJ (2000) Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem 275:36415–36422

    Article  CAS  PubMed  Google Scholar 

  • Madoux F, Janovick JA, Smithson D et al (2015) Development of a phenotypic high-content assay to identify pharmacoperone drugs for the treatment of primary hyperoxaluria type 1 by high-throughput screening. Assay Drug Dev Technol 13:16–24

    Article  CAS  PubMed  Google Scholar 

  • Mandrile G, van Woerden CS, Berchialla P et al (2014) Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int 86:1197–1204

    Article  CAS  PubMed  Google Scholar 

  • Martin-Higueras C, Luis-Lima S, Salido E (2016) Glycolate oxidase is a safe and efficient target for substrate reduction therapy in a mouse model of primary hyperoxaluria type I. Mol Ther 24:719–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mesa-Torres N, Salido E, Pey AL (2014a) The lower limits for protein stability and foldability in primary hyperoxaluria type I. Biochim Biophys Acta 1844:2355–2365

    Article  CAS  PubMed  Google Scholar 

  • Mesa-Torres N, Tomic N, Albert A, Salido E, Pey AL (2015) Molecular recognition of PTS-1 cargo proteins by Pex5p: implications for protein mistargeting in primary hyperoxaluria. Biomol Ther 5:121–141

    CAS  Google Scholar 

  • Mesa-Torres N, Yunta C, Fabelo-Rosa I et al (2014b) The consensus-based approach for gene/enzyme replacement therapies and crystallization strategies: the case of human alanine-glyoxylate aminotransferase. Biochem J 462:453–463

    Article  CAS  PubMed  Google Scholar 

  • Miyata N, Steffen J, Johnson ME, Fargue S, Danpure CJ, Koehler CM (2014) Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1. Proc Natl Acad Sci 111:14406–14411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monico CG, Rossetti S, Olson JB, Milliner DS (2005) Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 67:1704–1709

    Article  CAS  PubMed  Google Scholar 

  • Mulay SR, Kulkarni OP, Rupanagudi KV et al (2013) Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. J Clin Invest 123:236–246

    Article  CAS  PubMed  Google Scholar 

  • Nayak S, Herzog RW (2010) Progress and prospects: immune responses to viral vectors. Gene Ther 17:295–304

    Article  CAS  PubMed  Google Scholar 

  • Neef DW, Turski ML, Thiele DJ (2010) Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol 8:e1000291

    Article  PubMed  PubMed Central  Google Scholar 

  • Nguyen GN, George LA, Siner JI, et al (2016) Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A. J Thromb Haemost doi:10.1111/jth.13543

  • Ohashi T (2012) Enzyme replacement therapy for lysosomal storage diseases. Pediatr Endocrinol Rev 10(Suppl 1):26–34

    PubMed  Google Scholar 

  • Oppici E, Fargue S, Reid ES et al (2015) Pyridoxamine and pyridoxal are more effective than pyridoxine in rescuing folding-defective variants of human alanine:glyoxylate aminotransferase causing primary hyperoxaluria type I. Hum Mol Genet 24:5500–5511

    Article  CAS  PubMed  Google Scholar 

  • Pey AL, Albert A, Salido E (2013) Protein homeostasis defects of alanine-glyoxylate aminotransferase: new therapeutic strategies in primary hyperoxaluria type I. Biomed Res Int 2013:687658

    Article  PubMed  PubMed Central  Google Scholar 

  • Purdue PE, Takada Y, Danpure CJ (1990) Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol 111:2341–2351

    Article  CAS  PubMed  Google Scholar 

  • Roncador A, Oppici E, Talelli M et al (2016) Use of polymer conjugates for the intraperoxisomal delivery of engineered human alanine:glyoxylate aminotransferase as a protein therapy for primary hyperoxaluria type I. Nanomedicine 13:897–907

    Article  PubMed  Google Scholar 

  • Salido E, Pey AL, Rodriguez R, Lorenzo V (2012) Primary hyperoxalurias: disorders of glyoxylate detoxification. Biochim Biophys Acta 1822:1453–1464

    Article  CAS  PubMed  Google Scholar 

  • Salido E, Rodriguez-Pena M, Santana A, Beattie SG, Petry H, Torres A (2011) Phenotypic correction of a mouse model for primary hyperoxaluria with adeno-associated virus gene transfer. Mol Ther 19:870–875

    Article  CAS  PubMed  Google Scholar 

  • Salido EC, Li XM, Lu Y et al (2006) Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer. Proc Natl Acad Sci U S A 103:18249–18254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sikora P, von Unruh GE, Beck B et al (2008) [13C2]oxalate absorption in children with idiopathic calcium oxalate urolithiasis or primary hyperoxaluria. Kidney Int 73:1181–1186

    Article  CAS  PubMed  Google Scholar 

  • Smid BE, Aerts JMFG, Boot RG, Linthorst GE, Hollak CEM (2010) Pharmacological small molecules for the treatment of lysosomal storage disorders. Expert Opin Investig Drugs 19:1367–1379

    Article  CAS  PubMed  Google Scholar 

  • Terlecky SR, Koepke JI (2007) Drug delivery to peroxisomes: employing unique trafficking mechanisms to target protein therapeutics. Adv Drug Deliv Rev 59:739–747

    Article  CAS  PubMed  Google Scholar 

  • van Woerden CS, Groothoff JW, Wanders RJA, Davin J-C, Wijburg FA (2003) Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant 18:273–279

    Article  PubMed  Google Scholar 

  • van Woerden CS, Groothoff JW, Wijburg FA et al (2007) Primary hyperoxaluria remains undiagnosed in patients with hyperoxaluria and recurrent urolithiasis. Clin Chem 53:1553–1555

    Article  PubMed  Google Scholar 

  • Yabe Y, Nishikawa M, Tamada A, Takakura Y, Hashida M (1999) Targeted delivery and improved therapeutic potential of catalase by chemical modification: combination with superoxide dismutase derivatives. J Pharmacol Exp Ther 289:1176–1184

    CAS  PubMed  Google Scholar 

  • Yamamoto H, Fukui K, Takahashi H et al (2009) Roles of Tom70 in import of presequence-containing mitochondrial proteins. J Biol Chem 284:31635–31646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zapata-Linares N, Rodriguez S, Salido E et al (2016) Generation and characterization of human iPSC lines derived from a primary hyperoxaluria type I patient with p.I244T mutation. Stem Cell Res 16:116–119

    Article  CAS  PubMed  Google Scholar 

  • Zhao F, Bergstralh EJ, Mehta RA et al (2016) Predictors of incident ESRD among patients with primary Hyperoxaluria presenting prior to kidney failure. Clin J Am Soc Nephrol 11:119–126

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by grant SAF2015-69796 from the Spanish Ministry of Science.

Author information

Authors and Affiliations

  1. Department of Pathology & Nephrology, Centre for Biomedical Research on Rare Diseases (CIBERER) Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain

    Cristina Martin-Higueras, Armando Torres & Eduardo Salido

  2. Department of Pathology, ULL School Medicine, 38320, Tenerife, Spain

    Eduardo Salido

Authors
  1. Cristina Martin-Higueras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Armando Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eduardo Salido
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eduardo Salido.

Ethics declarations

Conflict of interest

None.

Additional information

Communicated by: Carlo Dionisi-Vici

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin-Higueras, C., Torres, A. & Salido, E. Molecular therapy of primary hyperoxaluria. J Inherit Metab Dis 40, 481–489 (2017). https://doi.org/10.1007/s10545-017-0045-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-017-0045-3

Keywords

Search

Navigation