Molecular therapy of primary hyperoxaluria

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.

Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria

“…Glyoxylate is converted into either glycine by AGT, glycolate by GRHPR, or oxalate by lactate dehydrogenase (LDH; encoded by the LDHA gene in the liver). Reduced AGT or GRHPR activity leads to an increased accumulation of glyoxylate and a subsequent over-production of oxalate 1, 2, 3, 4, 5, 6, 7, 8, 9, 10Figure 1Identification of siRNAs Targeting Ldha or Hao1 for Study of PH(A) Oxalate metabolism pathway overview.…”

Recurrent primary hyperoxaluria type 2 leads to early post‑transplant renal function loss: A case report

“…Conservative measures, including adequate hydration and oral citrate supplementation, are essential to preserve renal function and prevent nephrolithiasis for patients with early hyperoxaluria ( 4 ). Molecular targeted therapy is still currently being explored in cell systems and animal models, but has not been fully investigated in humans ( 9 ).…”

The Value of Mouse Models of Rare Diseases: A Spanish Experience

“…The Agxt TM 1 Ull mouse reproduces the main PH1 features ( Salido et al, 2006 ) and has been used to evaluate promising experimental therapies ( Martin-Higueras et al, 2017 ). Regulation of oxalate transepithelial flux in the gut following intestinal colonization with Oxalobacter ( Hatch et al, 2011 ) has received an innovative new drug designation by the United States Food and Drug Administration and is in clinical trials.…”