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… 
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67 Citations

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.
CRISPR/Cas9-mediated metabolic pathway reprogramming in a novel humanized rat model ameliorates primary hyperoxaluria type 1.
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.
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References

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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.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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