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Query: UMLS:C0020500 (hyperoxaluria)
 912 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.
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PMID:An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria. 2953 12

Oxalate (Ox) is an end-product of metabolism, important for poor solubility of its calcium salt in biological fluids. Ox can therefore be found in about 70% of urinary calculi. Hyperoxaluria (HOx) defined as Ox exceeding 0.5 mmol)/day, may cause nephrolithiasis/nephrocalcinosis and may be classified as dietary (DH), enteric (EH) or primary (PH). Fractional intestinal absorption of Ox is less than 10%, but increases to over 20% at calcium intakes below 200 mg/day. DH is often related to low-calcium diets. EH is caused by non-absorbed fatty acids which bind to calcium and lower its concentration in the intestinal lumen. Ox forms more soluble complexes with other cations and results in HOx. Similar mechanisms may cause HOx following bariatric surgery. PHs are the most severe causes of HOx. Three types have so far been described, all being autosomic recessive. PH1 is due to mutations of AGXT gene encoding liver alanine-glyoxylate aminotransferase, PH2 is caused by mutations of GR-HPR gene encoding glyoxylate reductase and PH3 by mutations of HOGA1 encoding for hydroxyl-oxoglutarate aldolase. HOx results from deficient detoxification from glyoxylate, which is oxidized to Ox. The three PHs have different severity, though not always clinically distinguishable. They are identified through genetics and, in PH1, good genotype/phenotype correlations have been established. Thanks to early biochemical and genetic diagnosis, which are crucial to either prevent progression to ESRF or choose adequate transplantation strategies, the outlook of PH patients has dramatically improved in the last decades and will furtherly do in view of new therapeutic strategies.
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PMID:[The Hyperoxalurias]. 2796 20

This perspective focuses on how the gut microbiota can impact urinary oxalate excretion in the context of hyperoxaluria, a major risk factor in kidney stone disease. In the genetic disease of Primary Hyperoxaluria Type 1 (PH1), an increased endogenous production of oxalate, due to a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGT), results in hyperoxaluria and oxalate kidney stones. The constant elevation in urinary oxalate in PH1 patients ultimately leads to tissue deposition of oxalate, renal failure and death and the only known cure for PH1 is a liver or liver-kidney transplant. The potential impact of a probiotic/therapeutic approach may be clinically significant in PH1 and could also extend to a much larger population of idiopathic oxalate stone formers who comprise ~12% of Americans, individuals with enteric hyperoxaluria, and an emerging population of hyperoxaluric patients who have undergone bariatric surgery and develop kidney stone disease as a consequence.
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PMID:Gut microbiota and oxalate homeostasis. 2821 1


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