Publications by authors named "Cristina Martin-Higueras"

11 Publications

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Is stiripentol truly effective for treating primary hyperoxaluria?

Clin Kidney J 2021 Jan 25;14(1):442-444. Epub 2020 May 25.

Department of Pediatrics, Division of Pediatric Nephrology, University Children's Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

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http://dx.doi.org/10.1093/ckj/sfaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857785PMC
January 2021

Inherited conditions resulting in nephrolithiasis.

Curr Opin Pediatr 2020 04;32(2):273-283

Institute of Experimental Immunology, University Hospital Bonn, Germany.

Purpose Of Review: Prevalence of pediatric urolithiasis is increasing, which is definitively visible in increasing numbers of presentations in emergency or outpatient clinics. In pediatric patients, a genetic or metabolic disease has to be excluded, so that adequate treatment can be installed as early as possible. Only then either recurrent stone events and chronic or even end-stage kidney disease can be prevented.

Recent Findings: The genetic background of mostly monogenic kidney stone diseases was unravelled recently. In hypercalcuria, for example, the commonly used definition of idiopathic hypercalciuria was adopted to the genetic background, here three autosomal recessive hereditary forms of CYP24A1, SLC34A1 and SLC34A3 associated nephrocalcinosis/urolithiasis with elevated 1.25-dihydroxy-vitamin D3 (1.25-dihydroxy-vitamin D3) (calcitriol) levels. In addition either activating or inactivating mutations of the calcium-sensing receptor gene lead either to hypocalcemic hypercalciuria or hypercalcemic hypocalciuria. In primary hyperoxaluria, a third gene defect was unravelled explaining most of the so far unclassified patients. In addition, these findings lead to new treatment options, which are currently evaluated in phase III studies.

Summary: Kidney stones are not the disease itself, but only its first symptom. The underlying disease has to be diagnosed in every pediatric patient with the first stone event.
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http://dx.doi.org/10.1097/MOP.0000000000000848DOI Listing
April 2020

Systemic Alanine Glyoxylate Aminotransferase mRNA Improves Glyoxylate Metabolism in a Mouse Model of Primary Hyperoxaluria Type 1.

Nucleic Acid Ther 2019 04 24;29(2):104-113. Epub 2019 Jan 24.

1 Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut.

Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. Loss of alanine glyoxylate aminotransferase (AGT) function to convert intermediate metabolite glyoxylate to glycine causes the accumulation and reduction of glyoxylate to glycolate, which eventually is oxidized to oxalate. Excess oxalate in PH1 patients leads to the formation and deposition of calcium oxalate crystals in the kidney and urinary tract. Oxalate crystal deposition causes a decline in renal function, systemic oxalosis, and eventually end-stage renal disease and premature death. mRNA-based therapies are a new class of drugs that work by replacing the missing enzyme. mRNA encoding AGT has the potential to restore normal glyoxylate to glycine metabolism, thus preventing the buildup of calcium oxalate in various organs. Panels of codon-optimized AGT mRNA constructs were screened in vitro and in wild-type mice for the production of a functional AGT enzyme. Two human constructs, wild-type and engineered AGT (RHEAM), were tested in Agxt mice. Repeat dosing in Agxt mice resulted in a 40% reduction in urinary oxalate, suggesting therapeutic benefit. These studies suggest that mRNA encoding AGT led to increased expression and activity of the AGT enzyme in liver that translated into decrease in urinary oxalate levels. Taken together, our data indicate that AGT mRNA may have the potential to be developed into a therapeutic for PH1.
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http://dx.doi.org/10.1089/nat.2018.0740DOI Listing
April 2019

CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I.

Nat Commun 2018 12 21;9(1):5454. Epub 2018 Dec 21.

Regenerative Medicine Program, Center for Applied Medical Research (CIMA), University of Navarra, IdiSNA, Pamplona, 31008, Spain.

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1 mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites.
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http://dx.doi.org/10.1038/s41467-018-07827-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303323PMC
December 2018

Targeting kidney inflammation as a new therapy for primary hyperoxaluria?

Nephrol Dial Transplant 2019 06;34(6):908-914

Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

The primary hyperoxalurias (PHs) are inborn errors of glyoxylate metabolism characterized by endogenous oxalate overproduction in the liver, and thus elevated urinary oxalate excretion. The urinary calcium-oxalate (CaOx) supersaturation and the continuous renal accumulation of insoluble CaOx crystals yield a progressive decline in renal function that often ends with renal failure. In PH Type 1 (AGXT mutated), the most frequent and severe condition, patients typically progress to end-stage renal disease (ESRD); in PH Type 2 (GRHPR mutated), 20% of patients develop ESRD, while only one patient with PH Type 3 (HOGA1 mutated) has been reported with ESRD so far. Patients with ESRD undergo frequent maintenance (haemo)dialysis treatment, and finally must receive a combined liver-kidney transplantation as the only curative treatment option available in PH Type 1. In experimental models using oxalate-enriched chow, CaOx crystals were bound to renal tubular cells, promoting a pro-inflammatory environment that led to fibrogenesis in the renal parenchyma by activation of a NACHT, LRR and PYD domains-containing protein 3 (NALP3)-dependent inflammasome in renal dendritic cells and macrophages. Chronic fibrogenesis progressively impaired renal function. Targeting the inflammatory response has recently been suggested as a therapeutic strategy to treat not only oxalate-induced crystalline nephropathies, but also those characterized by accumulation of cystine and urate in other organs. Herein, we summarize the pathogenesis of PH, revising the current knowledge of the CaOx-mediated inflammatory response in animal models of endogenous oxalate overproduction. Furthermore, we highlight the possibility of modifying the NLRP3-dependent inflammasome as a new and complementary therapeutic strategy to treat this severe and devastating kidney disease.
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http://dx.doi.org/10.1093/ndt/gfy239DOI Listing
June 2019

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1.

J Med Chem 2018 08 6;61(16):7144-7167. Epub 2018 Aug 6.

Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , Campus de Cartuja s/n , 18071 Granada , Spain.

Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00399DOI Listing
August 2018

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

Mol Ther 2018 08 15;26(8):1983-1995. Epub 2018 Jun 15.

Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA. Electronic address:

Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients. Using RNAi, we provide the first in vivo evidence in mammals to support LDH as the key enzyme responsible for converting glyoxylate to oxalate. In addition, we demonstrate that reduction of hepatic LDH achieves efficient oxalate reduction and prevents calcium oxalate crystal deposition in genetically engineered mouse models of PH types 1 (PH1) and 2 (PH2), as well as in chemically induced PH mouse models. Repression of hepatic LDH in mice did not cause any acute elevation of circulating liver enzymes, lactate acidosis, or exertional myopathy, suggesting further evaluation of liver-specific inhibition of LDH as a potential approach for treating PH1 and PH2 is warranted.
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http://dx.doi.org/10.1016/j.ymthe.2018.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094358PMC
August 2018

DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress.

PLoS One 2017 29;12(6):e0179456. Epub 2017 Jun 29.

Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.

Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates. UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway. The aim of the present study was to examine the effect of six variants in DPAGT1 detected in patients with DPAGT1-CDG, and the role of endoplasmic reticulum stress, as part of the search for therapeutic strategies to use against DPAGT1-CDG. The effect of the six mutations, i.e., c.358C>A (p.Leu120Met), c.791T>G (p.Val264Gly), c.901C>T (p.Arg301Cys), c.902G>A (p.Arg301His), c.1154T>G (p.Leu385Arg), and of the novel mutation c.329T>C (p.Phe110Ser), were examined via the analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. In addition, the transient expression of different mutations was analysed in COS-7 cells. The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane. The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG. Even so, the fibroblasts of patients with DPAGT1-CDG seemed to be more sensitive to the stressor tunicamycin. The present work improves our knowledge of DPAGT1-CDG and provides bases for developing tailored splicing and folding therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179456PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491010PMC
September 2017

Molecular therapy of primary hyperoxaluria.

J Inherit Metab Dis 2017 07 19;40(4):481-489. Epub 2017 Apr 19.

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

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.
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http://dx.doi.org/10.1007/s10545-017-0045-3DOI Listing
July 2017

Iohexol plasma clearance, a simple and reliable method to measure renal function in conscious mice.

Pflugers Arch 2016 09 17;468(9):1587-94. Epub 2016 Jun 17.

University of La Laguna, Instituto Tecnologías Biomédicas (ITB), Tenerife, Spain.

In mice, renal function evaluated by serum creatinine has limitations. Gold standard methods using radioactive markers are cumbersome. We aimed to develop the iohexol plasma clearance as a simple assessment of renal function in conscious mice. We used two groups of mice: testing and validation, formed by 16 animals (8 male and 8 female) each. Iohexol was injected intravenously into the tail vein (6.47 mg), and tail tip blood samples were collected at 1, 3, 7, 10, 15, 35, 55, and 75 min. Iohexol plasma clearances were calculated in two ways: (1) two-compartment model (CL2) using all time points and (2) one-compartment model (CL1) using only the last four points. In the testing group, CL1 overestimated the true clearance (CL2). Therefore, CL1 was recalculated applying a correction factor calculated as the ratio between CL2/CL1. The latter was considered as the simplified method. CL2 averaged 223.3 ± 64.3 μl/min and CL1 252.4 ± 76.4 μl/min, which lead to a CF of 0.89. Comparable results for CL2, CL1, and simplified method were observed in the validation group. Additionally, we demonstrated the capacity of the simplified method to quantitatively assess different degrees of renal function in three mouse models: hyperoxaluric-CKD (87.4 ± 28.3 μl/min), heminephrectomized (135-0 ± 50.5 μl/min), and obese (399.6 ± 112.1 μl/min) mice. We have developed a simple and reliable method to evaluate renal function in conscious mice under diverse clinical conditions. Moreover, the test can be repeated in the same animal, which makes the method useful to examine renal function changes over time.
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http://dx.doi.org/10.1007/s00424-016-1843-4DOI Listing
September 2016

Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I.

Mol Ther 2016 Apr 22;24(4):719-25. Epub 2015 Dec 22.

Department of Pathology, Centre for Biomedical Research on Rare Diseases (CIBERER), Tenerife, Spain.

Primary hyperoxaluria type 1 (PH1) is caused by deficient alanine-glyoxylate aminotransferase, the human peroxisomal enzyme that detoxifies glyoxylate. Glycolate is one of the best-known substrates leading to glyoxylate production, via peroxisomal glycolate oxidase (GO). Using genetically modified mice, we herein report GO as a safe and efficient target for substrate reduction therapy (SRT) in PH1. We first generated a GO-deficient mouse (Hao1(-/-)) that presented high urine glycolate levels but no additional phenotype. Next, we produced double KO mice (Agxt1(-/-) Hao1(-/-)) that showed low levels of oxalate excretion compared with hyperoxaluric mice model (Agxt1(-/-)). Previous studies have identified some GO inhibitors, such as 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1,2,3-thiadiazole (CCPST). We herein report that CCPST inhibits GO in Agxt1(-/-) hepatocytes and significantly reduces their oxalate production, starting at 25 µM. We also tested the ability of orally administered CCPST to reduce oxalate excretion in Agxt1(-/-) mice, showing that 30-50% reduction in urine oxalate can be achieved. In summary, we present proof-of-concept evidence for SRT in PH1. These encouraging results should be followed by a medicinal chemistry programme that might yield more potent GO inhibitors and eventually could result in a pharmacological treatment for this rare and severe inborn error of metabolism.
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http://dx.doi.org/10.1038/mt.2015.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886931PMC
April 2016