Inhibition of Glycolate Oxidase With Dicer-substrate siRNA Reduces Calcium Oxalate Deposition in a Mouse Model of Primary Hyperoxaluria Type 1

@article{Dutta2016InhibitionOG,
  title={Inhibition of Glycolate Oxidase With Dicer-substrate siRNA Reduces Calcium Oxalate Deposition in a Mouse Model of Primary Hyperoxaluria Type 1},
  author={Chaitali Dutta and Nicole Avitahl-Curtis and Natalie W. Pursell and Marita Larsson Cohen and Benjamin Holmes and Rohan Diwanji and Wei Zhou and Luciano Henrique Apponi and Martin L. Koser and Bo Ying and Dongyu Chen and Xue Shui and Utsav H. Saxena and Wendy A Cyr and Anee Shah and Naim Nazef and Weimin Wang and Marc T. Abrams and Henryk T. Dudek and Eduardo Salido and Bob D. Brown and Chengjung Lai},
  journal={Molecular Therapy},
  year={2016},
  volume={24},
  pages={770 - 778}
}
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutations of alanine-glyoxylate aminotransferase (AGT), a key hepatic enzyme in the detoxification of glyoxylate arising from multiple normal metabolic pathways to glycine. Accumulation of glyoxylate, a precursor of oxalate, leads to the overproduction of oxalate in the liver, which accumulates to high levels in kidneys and urine. Crystalization of calcium oxalate (CaOx) in the kidney ultimately results… 
An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria.
TLDR
The ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and a clear rationale for clinical trials with this compound are demonstrated.
Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria
Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I.
TLDR
GO is reported as a safe and efficient target for substrate reduction therapy (SRT) in PH1 and the ability of orally administered CCPST to reduce oxalate excretion in Agxt1(-/-) mice is tested, showing that 30-50% reduction in urine oxalates can be achieved.
Effect of Alanine Supplementation on Oxalate Synthesis.
Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1.
TLDR
An unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range is introduced, which means a potential use in the treatment of PH1.
Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing
TLDR
An Agxt-/- mouse model is created which resembles much of the clinical phenotype of PH1 patients and will be a useful tool in developing novel therapies for this devastating disease.
Knockdown of lactate dehydrogenase by adeno‐associated virus‐delivered CRISPR/Cas9 system alleviates primary hyperoxaluria type 1
TLDR
CRISPR/Cas9‐mediated LDH disruption may represent an applicable new strategy for alleviating PH1 for its long‐lasting effect and low editorial efficiency requirements.
Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria.
TLDR
This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.
Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening
TLDR
Six low-molecular-weight fragments identified by crystallography-based fragment screening that bind to two different sites on the HAO1 structure and represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity.
...
...

References

SHOWING 1-10 OF 34 REFERENCES
Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I.
TLDR
GO is reported as a safe and efficient target for substrate reduction therapy (SRT) in PH1 and the ability of orally administered CCPST to reduce oxalate excretion in Agxt1(-/-) mice is tested, showing that 30-50% reduction in urine oxalates can be achieved.
Alanine–glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer
TLDR
Subcellular fractionation and immunofluorescence studies revealed that, as in the human liver, the expressed wild-type human AGT1 was predominantly localized in mouse hepatocellular peroxisomes, whereas the most common mutant form of AGT 1 was localized predominantly in the mitochondria.
Hydroxyproline metabolism in mouse models of primary hyperoxaluria.
TLDR
Data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate in PH patients, and Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalates deposition in the kidneys.
Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1
TLDR
Repurposing the FDA-approved DECA may be a pharmacologic strategy to treat PH1 patients with mutations in AGT because an additional 75 missense mutations inAGT may also result in mistrafficking.
Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria
TLDR
The results pinpoint the expression of defective splice variant of glycolate oxidase as the cause of isolated asymptomatic glycolic aciduria, contributing to the development of novel approaches, namely, substrate reduction, for the treatment of primary hyperoxaluria type I.
Molecular Aetiology of Primary Hyperoxaluria Type 1
  • C. Danpure
  • Biology, Medicine
    Nephron Experimental Nephrology
  • 2004
TLDR
Improved understanding of the molecular aetiology of PH1 has led to significant improvements in all aspects of the clinical management of the disorder, including diagnosis, prenatal diagnosis and treatment.
Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter.
Oxalobacter colonization of rat intestine was previously shown to promote enteric oxalate secretion and elimination, leading to significant reductions in urinary oxalate excretion (Hatch et al.
Hyperoxaluria Is Reduced and Nephrocalcinosis Prevented with an Oxalate-Degrading Enzyme in Mice with Hyperoxaluria
TLDR
The data suggest that oral therapy with OxDc-CLEC may reduce hyperoxaluria, prevent calcium oxalate nephrocalcinosis and urolithiasis, and can represent a realistic option for the treatment of human hyperoxAluria, independent of cause.
Primary hyperoxaluria type 1: still challenging!
TLDR
Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established end-stage renal disease (ESRD), and minimization of the time on dialysis will improve both the patient’s quality of life and survival.
Efficacy and safety of Oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria.
  • B. Hoppe, J. Groothoff, D. Milliner
  • Medicine
    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
  • 2011
TLDR
O. formigenes (Oxabact) was found to significantly reduce urine and plasma oxalate and was safe and well tolerated, however, as no significant change in Uox was seen, further studies to evaluate the efficacy of Oxabact treatment are needed.
...
...