RARE DISEASE
Primary hyperoxaluria type 1
Primary hyperoxaluria type 1
Primary hyperoxaluria type 1
Synonyms: Glycolic aciduria, Peroxisomal alanine-glyoxylate aminotransferase deficiency
Synonyms: Glycolic aciduria, Peroxisomal alanine-glyoxylate aminotransferase deficiency
Synonyms: Glycolic aciduria, Peroxisomal alanine-glyoxylate aminotransferase deficiency
Drug discovery
6
drugs
With orphan designations
Overview
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by mutations in the AGXT gene, leading to deficient alanine-glyoxylate aminotransferase activity. This results in hepatic overproduction of oxalate, causing recurrent calcium oxalate kidney stones, nephrocalcinosis, and progressive chronic kidney disease. Over 70% of patients develop end-stage renal disease (ESRD), often requiring dialysis or transplantation. Systemic oxalosis occurs when glomerular filtration rate drops below 30–45 mL/min, depositing oxalate in bones, retina, and cardiovascular tissues [1][2][6][11].
Population
Burden
Clinical: Median 12.8 lifetime hospital days, 3.6 hospitalizations, and 5+ urologic procedures (ureteroscopy/PCNL) [4][9].
Economic: Annual healthcare costs 6.5× higher vs matched controls, driven by dialysis ($4,530) and outpatient care ($13,894) [9].
Mortality: Up to 50% mortality within 5 years of ESRD without transplantation [4][10].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
603 drug discovery papers about Primary hyperoxaluria type 1, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
603 drug discovery papers about Primary hyperoxaluria type 1, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-28 | Data from the French Daily-Luma cohort suggest predictors of a lumasiran response.
Primary Hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disorder with genotype/phenotype correlation. The RNA interfering therapy lumasiran has revolutionized its prognosis but with heterogeneous response amongst patients. Here, we assessed a possible association between genotype and lumasiran response. In the ongoing French DAILY-LUMA cohort evaluating real-life efficacy and safety of lumasiran, we collected data at treatment initiation and at months three, six and 12 of treatment. The main outcomes were composite criteria, namely normalization and/or reduction over 30% from baseline in the urinary ratio of oxalate and creatinine (UOx/Creat) or in blood oxalate levels (POx) in patients with estimated glomerular filtration rate (eGFR) over or under 30 mL/min/1.73 m2, respectively. The primary endpoint was the proportion of patients reaching this criterion at three months, and secondary endpoints were the same analysis at six and 12 months. Genotype was classified into three groups depending on the vitamin B6 response: resistance, sensitivity, uncertain response (Ile244Thr variant of alanine-glyoxylate aminotransferase). In total, 76 patients (54 children) were included, at a median (inter quartile range) age at lumasiran initiation of 13 (4-33) years with 24 patients on dialysis. After three months treatment, 73 % of patients met the primary endpoint (% calculated on available data). There was no significant association between the underlying genotype and lumasiran response, albeit with a trend towards a lesser response in vitamin B6- sensitive forms. The only significant determinants found to be associated with the primary outcome were age at diagnosis and age at lumasiran initiation, the best response being observed in pediatric patients. Our study suggests a better response to lumasiran in children independent of the underlying genotype. In patients with pyridoxine sensitivity, we suggest continuing or initiating pyridoxine even after lumasiran initiation. After lumasiran initiation, a close follow-up and re-evaluation should be systematically performed.
2026-09-10 | Two Hereditary Renal Diseases In The Same Algerian Family: A Rare Case Report
Introduction: Primary hyperoxaluria type 1 (PH1) is the most frequent and severe form of primary hyperoxalurias. It is a rare autosomal recessive disease caused by an enzymatic deficiency in alanine-glyoxylate aminotransferase (AGT). Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition characterized by the development in adulthood, but in 72% of cases during the second decade, of multiple cysts in the kidneys and very often in the liver. It is the most common hereditary renal disease worldwide. Patients and Methods: Patient M.S., an 11-year-old boy from a first-degree consanguineous marriage, only son of two siblings originating from northern Algeria, with a family history of a sister and mother affected by ADPKD, diagnosed at 12 and 20 years respectively. The child consulted for bilateral renal colic associated with recurrent urinary tract infections beginning at the age of two years with stone expulsion. Clinical examination revealed a child in good general condition, no growth retardation, normal blood pressure at 110/70 mmHg, polyuria greater than 3 L/day. Urinalysis showed morning pH at 5.5, the rest without abnormalities. Laboratory blood and urine tests including complete blood count, renal function, serum electrolytes, calcium-phosphorus, liver and lipid profiles were normal. Calciuria was 1.08 mmol/L and hyperoxaluria was 449 mmol/L. The crystalline composition of expelled stones was whewellite (calcium oxalate monohydrate). Morphological assessment with plain abdominal X-ray and abdominopelvic ultrasound revealed nephrocalcinosis. Molecular analysis was performed by direct sequencing of exons 1, 4, 7, and 10 of the AGXT gene. The proband was homozygous for the c.853C>T (p.Ile244Thr) mutation, known as the "Maghrebian" mutation [Nagara et al., 2013; Belhaj et al., 2011]. Both parents were heterozygous for this mutation, and the sister did not carry the mutation. The child was started on diuretic therapy and pyridoxine at 500 mg/day, with significant improvement in oxalemia and oxaluria levels measured one year later. Discussion and Conclusion: This is a first-degree consanguineous family presenting two hereditary renal diseases that can lead to extrarenal replacement therapy. A detailed literature review on the Maghrebian mutation of PH1 and the studied populations [Nagara et al., 2013; Belhaj et al., 2011], as well as the rare observations of an association of two genetic renal diseases described in the same family, was performed. The dual hereditary renal involvement in this family posed the problem of genetic counseling and living-related renal transplantation. As the mother and sister have ADPKD, they cannot serve as kidney donors. The father remains the only potential donor. The development of cadaveric organ transplantation in our country remains the only hope for this family.
2026-05-27 | Targeting the Highly Deleterious G161C and Y260C SNP Variants of the AGXT Protein Involved in Glyoxylate Metabolism Using Tauroursodeoxycholic Acid: A Computational Study.
Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by mutations in the AGXT gene, leading to impaired glyoxylate metabolism and excessive oxalate accumulation, resulting in nephrolithiasis, nephrocalcinosis, and end-stage renal disease. As a rare and often neglected disease, PH1 poses a significant challenge to modern healthcare systems due to its progressive nature and limited therapeutic options. In this study, an integrated in silico approach was employed to identify pathogenic single-nucleotide polymorphisms (SNPs) and evaluate potential therapeutic candidates. Computational analyses using ConSurf, Align-GVGD, INPS-MD, CUPSAT, and iStable identified G161C and Y260C as highly deleterious variants affecting protein stability. Virtual screening, followed by ADME and toxicity assessments, identified Tauroursodeoxycholic acid (TUDCA) as a promising candidate with favorable pharmacokinetic and safety profiles. Molecular docking revealed that TUDCA exhibited higher binding affinity than the reference drug pyridoxine across native and SNP variants of AGXT proteins. Molecular dynamics simulations (300 ns) demonstrated enhanced structural stability of TUDCA-bound complexes, indicated by reduced RMSD and RMSF, improved compactness, and sustained hydrogen bonding. Furthermore, free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) analyses confirmed improved conformational stability and coordinated residue motions in SNP variant structures. Overall, these findings suggest that TUDCA may effectively stabilize structural alterations induced by pathogenic AGXT variants, highlighting its potential as a precision medicine-based therapeutic strategy for PH1.
2026-01-02 | Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase (AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase (GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate metabolism, have shown promise in reducing oxalate burden. However, recently approved siRNA therapies remain limited by high cost, unfavorable pharmacokinetics, and limited global accessibility. We report the development of compound 2, a dual GO/LDHA inhibitor (Ki = 390 and 40 nM, respectively) that also promotes hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy was evaluated in Agxt-/- mice, both in primary hepatocytes and through oral administration. Treatment significantly reduced hepatic LDHA levels, urinary oxalate excretion, and renal calcium-oxalate crystal deposition. These findings support compound 2 as a first-in-class, orally bioavailable small molecule with dual inhibitory and proteolytic activity, offering a novel therapeutic candidate for PH1 and other oxalate-related pathologies.
2025-09-11 | Primary Hyperoxaluria Type 1: An Unexpected Diagnosis after Kidney Transplantation.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by a deficiency of the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase, which catalyzes the conversion of glyoxylate to glycine, resulting in increased oxalate production. The clinical consequences of the progressive buildup of oxalates include nephrocalcinosis, nephrolithiasis, chronic kidney disease, and ultimately, renal failure with extra-renal involvement. The diagnosis of PH1 is challenging due to the non-specific nature of its symptoms and the need for costly genetic testing. For many years, the management of PH1 was mainly supportive care. Currently, we have access to novel RNA interference (RNAi) therapeutics, such as lumasiran and nedosiran, which reduce hepatic oxalate production; however, they are prohibitively expensive in most countries. The only curative treatment is liver transplantation, and in cases that progress to end-stage kidney disease (ESKD), simultaneous dual kidney and liver transplantation is usually indicated. We present a case of a 46-year-old woman admitted to our clinic on the eighth day of post-kidney transplantation for evaluating the causes of delayed graft function. During the diagnostic work-up, PH1 was diagnosed. A biopsy of the transplanted kidney also revealed microvascular inflammation (MVI). The patient was treated with fluid therapy, a restrictive diet, pyridoxine, and initially, intensive hemodialysis. Given the identification of a genetic variant of the disease that responds well to pyridoxine treatment, and considering the exceedingly high cost of lumasiran therapy, this medication was not utilized. In addition, it was decided to administer methylprednisolone pulses, plasmapheresis, and immunoglobulin infusions in response to MVI. This treatment resulted in improvements in both clinical and laboratory parameters. PH1 is a rare cause of calcium oxalate nephrolithiasis and nephrocalcinosis and should be considered in the differential diagnosis of patients with progressive renal failure. This case highlights the importance of early diagnosis, which allows optimal supportive and/or RNAi therapy and appropriate qualification for kidney transplantation in cases of ESKD. This is particularly important as isolated kidney transplantation (without concomitant liver transplantation) can lead to rapid loss of graft function and may ultimately prove futile.
cell therapies
2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2026-01-13 | Don’t think that combined liver–kidney transplant can solve everything in primary hyperoxaluria type 1!
Sandrine Lemoine, Anne-Laure Sellier-Leclerc, Alice Koenig, Charlène Levi, Justine Bacchetta; Don’t think that combined liver kidney transplant can solve e
2025-12-15 | Combined liver and kidney transplantation: Experience and outcomes at Baskent university
Introduction Combined liver and kidney transplantation (CLKT) is a complex but essential procedure in selected patients with dual organ failure. We present our single-center experience with CLKT in children and adults. Materials and Methods We retrospectively analyzed 11 patients who underwent CLKT at our center between 1988 and 2024 regarding demographic and clinical data, including age, sex, transplant type (simultaneous/sequential), etiology, dialysis status, graft/patient survival, rejection, and oxalate levels. We also evaluated lymphocyte cross-match, panel reactive antibody screening, and complement-dependent cytotoxicity testing. Results Patients included 7 female and 4 male patients (mean age 18 years); 8 were pediatric and 3 were adult recipients. One patient with primary hyperoxaluria underwent a simultaneous liver-kidney transplant, and 10 patients received sequential transplants. Six patients were diagnosed with primary hyperoxaluria. The patient with simultaneous deceased donor transplant experienced early graft loss due to oxalate deposition and humoral rejection. Four patients experienced kidney graft rejection (1 cellular, 3 humoral). One patient with cryptogenic cirrhosis and persistent hepatorenal syndrome died from sepsis in the early postoperative period. A patient with progressive familial intrahepatic cholestasis later developed focal segmental glomerulosclerosis, which was potentially related to long-term tacrolimus exposure. Another patient required graft nephrectomy following thrombotic microangiopathy. The remaining 8 patients had favorable long-term outcomes without significant complications. Conclusions Our experience supports the staged transplant approach for hyperoxaluria and highlights the importance of individualized immunosuppressive strategies. Renal grafts were more susceptible, underscoring the need for vigilant immunologic assessment. Further multicenter studies are warranted to optimize transplant timing and improve outcomes in this complex patient population.
2024-09-01 | 364.13: Life-saving liver transplant procedure for pediatric and adult patients: Domino liver transplantation.
Introduction: Organ shortages made it clear that liver transplantation (LT) alone was an inadequate method. Domino liver transplantation (DLT) is the use of an explanted liver from patients with a limited number of liver diseases, such as metabolic enzyme defect, as a graft for other suitable patients. DLT can be a important option for patients with low chances on the waiting list and who do not have a suitable donor to live a healthy life. In this study, we presented three DLT and their results. Method: Case-1: First patient was a 12-year-old girl with primary hyperoxaluria type-1 (PH1). Liver function tests and liver biopsy was normal. We performed left lobe LT from his mother and transplanted the liver, which was obtained from this girl with PH-1, to another 55-year-old patient with cryptogenic liver cirrhosis and hepatocellular carcinoma (HCC). Both patients were successfully discharged. Case-2: The patient was a 5-year-old boy and was diagnosed with propionic acidemia (PA). He had epilectic discharges and had to eat a protein-restricted diet. Liver function tests and biopsy were normal. We performed left lobe LT from his mother. We transplanted the liver we obtained from the patient with PA to our 6-year-old girl, who we transplanted liver for metabolic liver disease from her father 2 years ago but is currently in the process of chronic rejection. The recipients were discharged on postoperative day 8. Case-3: A 2-year-old patient with mapple syrup urine disease (MSUD) underwent left lateral lobe LT from his father. Since the patient’s liver function tests were normal and the biopsy was normal, we transplanted the liver graft obtained from the patient to a 6-year-old boy with familial hypercholesterolemia. Both patients were successfully discharged on postoperative day 9. Results: The patient with PH1 underwent kidney transplantation (KT) 1 month after LT. Eight months after KT, serum creatinine value was 0.8 mg/dL and there was no evidence of oxalate calculi in radiologic evaluations. The total bilirubin (T.bil) level of the patient diagnosed with HCC decreased from 3.7 mg/dl to 0.8 mg/dl in the first month after LT. Patients with PA and MSUD were not subjected to any dietary restriction after LT. In addition, no neurologic complications such as seizures were observed after LT. T.bil level of the patient diagnosed with metabolic liver disease after LT decreased from 26.7 mg/dl to 0.8 mg/dl in the 4th postoperative month. The total cholesterol value of the patient with familial hypercholesterolemia decreased from 755 mg/dl to 263 mg/dl on postoperative day 8. Conclusion: Domino LT, if performed carefully by selecting the right patients with the right indications, can be an important graft source for patients who do not have a suitable donor and are on the waiting list for liver transplantation.
2024-04-05 | Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the AGXT gene. Combined liver and kidney transplantation is currently the only permanent curative treatment. We combined locus-specific gene correction and hepatic direct cell reprogramming to generate autologous healthy induced hepatocytes (iHeps) from PH1 patient-derived fibroblasts. First, site-specific AGXT corrected cells were obtained by homology directed repair (HDR) assisted by CRISPR-Cas9, following two different strategies: accurate point mutation (c.731T>C) correction or knockin of an enhanced version of AGXT cDNA. Then, iHeps were generated, by overexpression of hepatic transcription factors. Generated AGXT-corrected iHeps showed hepatic gene expression profile and exhibited in vitro reversion of oxalate accumulation compared to non-edited PH1-derived iHeps. This strategy set up a potential alternative cellular source for liver cell replacement therapy and a personalized PH1 in vitro disease model.
proteins
2026-04-14 | Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.
Phosphorylation is a fundamental post-translational modification that contributes to the dynamic control of protein function and stability. More than 300,000 site-specific phosphorylation sites have been detected across > 20,000 human proteins, yet only a small fraction (~ 5%) have been experimentally characterized, and their roles in health and disease remain largely unexplored. In particular, the functional consequences of most phosphorylation events in metabolic enzymes remain unknown. Here, we investigated the functional impact of modifying Ser81 in alanine:glyoxylate aminotransferase (AGT), the key enzyme responsible for glyoxylate detoxification and whose loss-of-function causes Primary Hyperoxaluria Type I (PH1). We examined phosphomimetic substitutions at Ser81 in the WT (wild-type) enzyme, the common polymorphic minor allele (LM, containing two variations, p.P11L and p.I340M), and the two most frequent PH1-associated variants (LM-p.G170R and LM-p.I244T). Using biochemical, biophysical and cell-based approaches, we found that introducing a negative charge at Ser81 (through the S81D substitution) strongly perturbs PLP (pyridoxal 5´-phosphate)/PMP (pyridoxamine 5´-phosphate) binding pose and disrupts catalytic activity, while preserving secondary and tertiary structure as well as peroxisomal localization. In contrast, the non-charged S81A substitution produced milder effects. These results indicate that Ser81 contributes to stabilizing the cofactor interaction network at the AGT active site. Our findings therefore identify Ser81 as a previously uncharacterized regulatory position that can critically influence AGT activity. Although further work is required to determine the physiological frequency and regulatory context of this modification in vivo, our results suggest that phosphorylation at this position could represent an additional modulatory layer influencing AGT function and genotype-phenotype relationships in PH1, with potential implications for understanding regulatory mechanisms affecting AGT activity in disease.
2022-12-01 | Oxalate Chelating Activity of Egg White Proteins and Their Hydrolysates
Major egg white proteins and their hydrolysates serve as functional food ingredients that have certain metal-chelating properties. Employing egg white proteins and their hydrolysates to scavenge dietary oxalates is anticipated to have beneficial effect in the prevention of kidney stones. The objective of this study was to determine the biogenic oxalate-chelating activity of ovalbumin, ovomucin, and ovotransferrin and their hydrolysates. To prepare oxalate extracts, 30 mL of 0.25 N HCl was added to separately to 0.5 g of dried spinach and starfruit powders followed by boiling for 15 min, and after cooling, the addition of a further 20 mL of 0.25 N HCl. Having prepared these extracts, ovalbumin, ovomucin, and ovotransferrin and their hydrolysates were separately mixed with oxalate extracts and incubated at 3°C for 24 h. Following centrifugation, supernatants were analyzed by HPLC using a reverse-phase C18 column coupled with a diode array detector. We found that all assessed proteins and their hydrolysates showed biogenic oxalate-chelating activity against the oxalates of spinach. In contrast, however, only ovalbumin, ovalbumin-hydrolysate, and ovomucin showed chelating activity (57.10%±8.84%, 85.44%±5.30%, 73.20%±4.13%, respectively) against the oxalates of starfruit (P<0.05). Overall, hydrolyzed ovalbumin was identified as the most effective chelator of the oxalates both spinach and starfruit. In this study, we thus established that the assessed egg white proteins and their hydrolysates have oxalate-chelating activity in vitro, thereby indicating that these compounds have potential utility as nutraceuticals for the chelation of dietary oxalate. However, further research will be necessary to verify their oxalate-chelating activities against different fruits and vegetables and under specific in vivo conditions and against purified oxalate.
2021-11-25 | Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria Type 1 and end-stage renal disease: a Phase II study.
In primary hyperoxaluria Type 1 (PH1), endogenous oxalate overproduction significantly elevates urinary oxalate excretion, resulting in recurrent urolithiasis and/or progressive nephrocalcinosis and often early end-stage renal disease (ESRD). In ESRD, dialysis cannot sufficiently remove oxalate; plasma oxalate (Pox) increases markedly, inducing systemic oxalate deposition (oxalosis) and often death. Interventions to reduce Pox in PH1 subjects with ESRD could have significant clinical impact. This ongoing Phase II, open-label trial aimed to evaluate whether long-term Oxabact™ (Oxalobacter formigenes, OC5, OxThera Intellectual Property AB, Sweden) lowers Pox in PH1 ESRD subjects, ameliorating clinical outcome. PH1 ESRD subjects on stable dialysis regimens were examined. Subjects were administered one OC5 capsule twice daily for up to 36 months or until transplantation. Total Pox values, cardiac function and safety were evaluated. Free Pox was evaluated in a comparative non-treated PH1 dialysis group using retrospective chart reviews and analyses. Twelve subjects enrolled in an initial 6-week treatment phase. Following a washout of up to 4 weeks, eight subjects entered a continuation study; outcomes after 24 months of treatment are presented. After 24 months, all subjects had reduced or non-elevated Pox compared with baseline. Cardiac function improved, then stabilized. No treatment-related serious adverse events were reported. Compared with an untreated natural control cohort, 24 months OC5 administration was beneficial to PH1 ESRD subjects by substantially decreasing Pox concentrations, and improving or stabilizing cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated.
2020-10-01 | Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys
Short bowel (SB) increases the risk of kidney stones. However, the underlying mechanism is unclear. Here, we examined how SB affected renal oxalate and citrate handlings for in vivo hyperoxaluric rats and in vitro tubular cells. SB was induced by small intestine resection in male Wistar rats. Sham-operated controls had no resection. After 7 days of recovery, the rats were divided into control, SB (both fed with distilled water), ethylene glycol (EG), and SB+EG (both fed with 0.75% EG for hyperoxaluric induction) groups for 28 days. We collected the plasma, 24 h of urine, kidney, and intestine tissues for analysis. Hypocitraturia was found and persisted up to 28 days for the SB group. Hypocalcemia and high plasma parathyroid hormone (PTH) levels were found in the 28-day SB rats. SB aggravated EG-mediated oxalate nephropathy by fostering hyperoxaluria and hypocitraturia, and increasing the degree of supersaturation and calcium oxalate (CaOx) crystal deposition. These effects were associated with renal up-regulations of the oxalate transporter solute carrier family 26 (Slc26)a6 and citrate transporter sodium-dependent dicarboxylate cotransporter-1 (NaDC-1) but not Slc26a2. The effects of PTH on the SB kidneys were then examined in NRK-52E tubular cells. Recombinant PTH attenuated oxalate-mediated cell injury and up-regulated NaDC-1 via protein kinase A (PKA) activation. PTH, however, showed no additive effects on oxalate-induced Slc26a6 and NaDC-1 up-regulation. Together, these results demonstrated that renal NaDC-1 upregulation-induced hypocitraturia weakened the defense against Slc26a6-mediated hyperoxaluria in SB kidneys for excess CaOx crystal formation. Increased tubular NaDC-1 expression caused by SB relied on PTH.
2019-06-14 | Induction of enteric oxalate secretion by Oxalobacter formigenes in mice does not require the presence of either apical oxalate transport proteins Slc26A3 or Slc26A6
Oxalobacter sp. promotion of enteric oxalate excretion, correlating with reductions in urinary oxalate excretion, was previously reported in rats and mice, but the mechanistic basis for this affect has not been described. The main objective of the present study was to determine whether the apical oxalate transport proteins, PAT1 (slc26a6) and DRA (slc26a3), are involved in mediating the Oxalobacter-induced net secretory flux across colonized mouse cecum and distal colon. We measured unidirectional and net fluxes of oxalate across tissues removed from colonized PAT1 and DRA knockout (KO) mice and also across two double knockout (dKO) mouse models with primary hyperoxaluria, type 1 (i.e., deficient in alanine-glyoxylate aminotransferase; AGT KO), including PAT1/AGT dKO and DRA/AGT dKO mice compared to non-colonized mice. In addition, urinary oxalate excretion was measured before and after the colonization procedure. The results demonstrate that Oxalobacter can induce enteric oxalate excretion in the absence of either apical oxalate transporter and urinary oxalate excretion was reduced in all colonized genotypes fed a 1.5% oxalate-supplemented diet. We conclude that there are other, as yet unidentified, oxalate transporters involved in mediating the directional changes in oxalate transport across the Oxalobacter-colonized mouse large intestine.
oligonucleotides
2026-08-01 | A Case Report of Primary Hyperoxaluria Type 1 Diagnosed in a Geriatric Patient on Dialysis: Unique Clinical Course With Lumasiran
Primary hyperoxaluria (PH) is a group of rare autosomal recessive disorders of impaired hepatic glyoxylate metabolism. Primary hyperoxaluria type 1 (PH1), the most common and severe phenotype, results in incident kidney failure in most patients by young adulthood (1). The majority of PH1 patients are diagnosed around age 10 years, though a significant delay in diagnosis is common (2). Preventative treatment options have historically been limited to robust fluid intake, crystallization inhibitors, and pyridoxine.
2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
2026-05-04 | Isolated Kidney Transplant in Primary Hyperoxaluria-1 Enabled by Small Interfering RNA (siRNA) Therapy. Is It Time for Change? Case Report and Review of the Literature.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production that leads to nephrocalcinosis or nephrolithiasis and progressive kidney failure, associated with systemic oxalosis that is not reversed by dialysis. Pharmacological treatment is limited. Combined or sequential liver and kidney transplant is standard of care for PH1. Recently approved RNA-interference (RNAi) therapy with lumasiran or nedosiran targeting glycolate oxidase and lactate dehydrogenase A, respectively, reduces hepatic oxalate synthesis. This makes kidney-only (isolated) transplantation (iKT) a potentially successful, novel approach for managing PH1 patients with advanced kidney disease combined with hyperhydration, urine alkalinization, and vitamin B6 (where applicable). We analyzed the course of a young PH1 kidney transplant recipient at our institution and performed a literature review of patients with small interfering RNA-enabled iKT. A patient with PH1 due to a homozygous, pathogenic variant in AGXT exon 1 (c.121G>A; p.Gly41Arg) received a deceased donor kidney transplant after 6.5 years of hemodialysis and 4.3 years of RNAi therapy with lumasiran. He maintained good kidney allograft function 9 months post-transplant despite the occurrence of an asymptomatic calyceal stone within the graft prior to transition to adult nephrology care. At 14 months, he experienced a T cell-mediated rejection, associated with a rise in serum creatinine and plasma oxalate, and a partially obstructing stone. A review of all 10 accessible cases of RNAi-supported iKT, including our own, revealed several instances of kidney stone formation (20%), stent obstruction (20%), and mild, mostly transient crystal deposition in the graft (37.5%). This report enriches the limited experience of RNAi-enabled kidney-only transplantation in PH1. RNA interference therapy has the potential to challenge the current standard of dual liver and kidney transplantation in children and young adults with this devastating disease but requires uninterrupted access to the drug with individualized, eGFR and oxalate level adjusted dosing, continued vigilance, and reporting of long-term outcomes.
2026-05-01 | Rescue of Renal Function After Novel RNA Interference Therapy (Lumasiran) for Catastrophic Post–Kidney Transplant Recurrent Oxalate Nephropathy in Primary Hyperoxaluria Type 1
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive genetic disorder of hepatic glyoxylate metabolism leading to overproduction of oxalate commonly resulting in nephrocalcinosis, renal failure and subsequent systemic oxalosis. The advent of small interfering RNA (siRNA) therapies such as lumasiran and nedosiran could represent a paradigm shift in the management of PH1 and may avoid the need for liver transplantation in some. However, to date, limited evidence on the management of patients exists when the diagnosis of PH1 is made only after renal transplantation. This report details a case of late diagnosis of PH1 in a 23-year-old adult who only received the diagnosis after renal transplantation and subsequent declining graft function. Missed opportunities for genetic testing included no investigation of echogenic kidneys on ultrasound at presentation, and no consideration of the diagnosis at the first transplant biopsy despite oxalate deposition. Genotyping revealed a pyridoxine-resistant phenotype and the patient's transplant function was stabilised by the use of lumasiran. To our knowledge, this case represents the first time lumasiran has been reported as a salvage therapy in an adult patient who was only diagnosed with PH1 following renal transplantation. This case highlights the importance of genetic testing in young patients with otherwise unexplained renal disease and should inform future guidelines regarding salvage therapy in adult patients who receive a late diagnosis.
2026-04-28 | Late Diagnosis of Primary Hyperoxaluria Type 1 After Kidney Transplant
Primary hyperoxaluria type 1 is a rare and often unrecognized cause of renal allograft dysfunction and loss, particularly when renal disease is attributed to recurrent nephrolithiasis. We report the case of a 62-year-old woman with a history of bilateral nephrolithiasis and prolonged use of anti-inflammatory drugs who underwent kidney transplantation with immediate graft function and an initially favorable course. After an extended period of stability, late and progressive graft dysfunction occurred. Allograft biopsy demonstrated tubular injury associated with extensive calcium oxalate crystal deposition, suggesting oxalosis. Serum oxalate was 18.6 µmol/L, and urinary oxalate was 94.9 mg/24 h. Genotyping identified a homozygous pathogenic variant in the AGXT gene, confirming the diagnosis of primary hyperoxaluria type 1. Review of the medical history revealed nephrocalcinosis in native kidneys, and family screening identified a sibling with nephrolithiasis. Pharmacological-dose pyridoxine was initiated as first-line therapy based on the responsive genotype, followed by RNA interference therapy with lumasiran due to the high risk of graft loss, resulting in initial stabilization of graft function. This report emphasizes that primary hyperoxaluria type 1 should be considered in transplant recipients with a history of nephrolithiasis, even in adulthood, and that post-transplant identification has direct implications for graft prognosis, therapeutic approach, and family screening, highlighting the need for metabolic and genetic investigation in selected cases before transplantation.
other
2026-09-22 | Adeno-Associated Viral Vector (AAV)-Mediated In Vivo CRISPR-Cas9 Delivery.
CRISPR-based gene editing is a growing therapeutic strategy for modifying or silencing disease-causing genes. This chapter focuses on the in vivo delivery of CRISPR systems using recombinant adeno-associated viral (rAAV) vectors. Specifically, we detail a methodology using a rAAV vector carrying Staphylococcus aureus Cas9 (SaCas9) to target the murine Hao1 gene in liver parenchymal cells as a curative treatment for primary hyperoxaluria type 1 (PH1). We provide comprehensive protocols for plasmid design and cloning, rAAV production, animal administration, and evaluation of editing efficacy.
2026-06-16 | In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.
2026-04-13 | Novel AAV843 Vector-Mediated Gene Replacement Therapy Rescues Primary Hyperoxaluria Type I in Mice.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder resulting from mutations in the alanine-glyoxylate aminotransferase (AGXT) gene, leading to excessive systemic deposition of calcium oxalate. This condition is an important cause of end-stage renal disease in children and poses a serious threat to patient survival. Current therapeutic approaches are limited primarily to conservative management and organ transplantation, underscoring the need for more effective treatments. Gene replacement therapy represents a promising alternative strategy. In this study, Agxt-/- mice lacking exons 3-8 were characterized, confirming the complete loss of hepatic alanine-glyoxylate aminotransferase (AGT) expression and the presence of early-onset hyperoxaluria. Exposure to glyoxylic acid induced pronounced renal calcium oxalate crystal deposition, establishing a robust and previously unreported induction approach in gene-edited PH1 mouse models. Using this platform, human AGXT cDNA was delivered via the liver-tropic, low-immunogenic AAV843 vector, which has been employed in clinical trials for hemophilia. Gene therapy resulted in normalization of urinary oxalate levels, restoration of hepatic AGT expression, and significant attenuation of renal injury and nephrocalcinosis. These therapeutic effects were accompanied by significant suppression of key mediators involved in renal inflammation, necroptosis, and fibrosis. Moreover, transgene expression was highly specific to the liver and was not associated with hepatotoxicity. These results demonstrate that AAV843-mediated AGXT gene replacement is a safe and effective approach that achieves phenotypic correction in a murine model of PH1, warranting further evaluation in preclinical studies.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-12-03 | Genetic Correction of the Most Common Mutation Causing Primary Hyperoxaluria Restores Enzyme Localization and Oxalate Metabolism.
Our research aimed to model primary hyperoxaluria type 1 in vitro using a stem cell model and assess the potential of adenine base editors in correcting the most common pathogenic AGXT genetic variant, c.508G>A (Gly170Arg), which leads to oxalate accumulation due to alanine-glyoxylate aminotransferase mislocalization. Patient-derived fibroblasts were induced to pluripotent stem cells, genetically corrected with adenine base editing, and subsequently differentiated into hepatocyte-like cells in parallel with their non-corrected isogenic counterparts. Enzyme localization was assessed through immunocytochemistry and confocal microscopy. The key metabolites associated with the disease were analyzed using liquid chromatography-mass spectrometry to evaluate the metabolic phenotype. Finally, lipid nanoparticle formulations were designed and tested as an in vivo-applicable delivery method for base editors. All induced pluripotent stem cell lines successfully differentiated into hepatocyte-like cells and expressed essential hepatocyte markers, including ALB, HNF1A, and AGXT. Adenine base editor-mediated genetic correction of the pathogenic AGXT mutation restored enzyme localization into peroxisomes and diminished oxalate accumulation without significant off-target effects. Base editor mRNA and AGXT variant targeting single guide RNA encapsulated within lipid nanoparticles mediated gene correction in the hepatocyte-like cell model. Using an in vitro model of primary hyperoxaluria type 1, we showed that base editor-mediated genetic correction of the most common hyperoxaluria-causing variant corrects enzyme mislocalization from mitochondria to peroxisomes and improves metabolic function. These results propose gene correction as a potential therapeutic approach to hyperoxaluria.
small molecules
2026-09-28 | Data from the French Daily-Luma cohort suggest predictors of a lumasiran response.
Primary Hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disorder with genotype/phenotype correlation. The RNA interfering therapy lumasiran has revolutionized its prognosis but with heterogeneous response amongst patients. Here, we assessed a possible association between genotype and lumasiran response. In the ongoing French DAILY-LUMA cohort evaluating real-life efficacy and safety of lumasiran, we collected data at treatment initiation and at months three, six and 12 of treatment. The main outcomes were composite criteria, namely normalization and/or reduction over 30% from baseline in the urinary ratio of oxalate and creatinine (UOx/Creat) or in blood oxalate levels (POx) in patients with estimated glomerular filtration rate (eGFR) over or under 30 mL/min/1.73 m2, respectively. The primary endpoint was the proportion of patients reaching this criterion at three months, and secondary endpoints were the same analysis at six and 12 months. Genotype was classified into three groups depending on the vitamin B6 response: resistance, sensitivity, uncertain response (Ile244Thr variant of alanine-glyoxylate aminotransferase). In total, 76 patients (54 children) were included, at a median (inter quartile range) age at lumasiran initiation of 13 (4-33) years with 24 patients on dialysis. After three months treatment, 73 % of patients met the primary endpoint (% calculated on available data). There was no significant association between the underlying genotype and lumasiran response, albeit with a trend towards a lesser response in vitamin B6- sensitive forms. The only significant determinants found to be associated with the primary outcome were age at diagnosis and age at lumasiran initiation, the best response being observed in pediatric patients. Our study suggests a better response to lumasiran in children independent of the underlying genotype. In patients with pyridoxine sensitivity, we suggest continuing or initiating pyridoxine even after lumasiran initiation. After lumasiran initiation, a close follow-up and re-evaluation should be systematically performed.
2026-09-10 | Two Hereditary Renal Diseases In The Same Algerian Family: A Rare Case Report
Introduction: Primary hyperoxaluria type 1 (PH1) is the most frequent and severe form of primary hyperoxalurias. It is a rare autosomal recessive disease caused by an enzymatic deficiency in alanine-glyoxylate aminotransferase (AGT). Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition characterized by the development in adulthood, but in 72% of cases during the second decade, of multiple cysts in the kidneys and very often in the liver. It is the most common hereditary renal disease worldwide. Patients and Methods: Patient M.S., an 11-year-old boy from a first-degree consanguineous marriage, only son of two siblings originating from northern Algeria, with a family history of a sister and mother affected by ADPKD, diagnosed at 12 and 20 years respectively. The child consulted for bilateral renal colic associated with recurrent urinary tract infections beginning at the age of two years with stone expulsion. Clinical examination revealed a child in good general condition, no growth retardation, normal blood pressure at 110/70 mmHg, polyuria greater than 3 L/day. Urinalysis showed morning pH at 5.5, the rest without abnormalities. Laboratory blood and urine tests including complete blood count, renal function, serum electrolytes, calcium-phosphorus, liver and lipid profiles were normal. Calciuria was 1.08 mmol/L and hyperoxaluria was 449 mmol/L. The crystalline composition of expelled stones was whewellite (calcium oxalate monohydrate). Morphological assessment with plain abdominal X-ray and abdominopelvic ultrasound revealed nephrocalcinosis. Molecular analysis was performed by direct sequencing of exons 1, 4, 7, and 10 of the AGXT gene. The proband was homozygous for the c.853C>T (p.Ile244Thr) mutation, known as the "Maghrebian" mutation [Nagara et al., 2013; Belhaj et al., 2011]. Both parents were heterozygous for this mutation, and the sister did not carry the mutation. The child was started on diuretic therapy and pyridoxine at 500 mg/day, with significant improvement in oxalemia and oxaluria levels measured one year later. Discussion and Conclusion: This is a first-degree consanguineous family presenting two hereditary renal diseases that can lead to extrarenal replacement therapy. A detailed literature review on the Maghrebian mutation of PH1 and the studied populations [Nagara et al., 2013; Belhaj et al., 2011], as well as the rare observations of an association of two genetic renal diseases described in the same family, was performed. The dual hereditary renal involvement in this family posed the problem of genetic counseling and living-related renal transplantation. As the mother and sister have ADPKD, they cannot serve as kidney donors. The father remains the only potential donor. The development of cadaveric organ transplantation in our country remains the only hope for this family.
2026-05-27 | Targeting the Highly Deleterious G161C and Y260C SNP Variants of the AGXT Protein Involved in Glyoxylate Metabolism Using Tauroursodeoxycholic Acid: A Computational Study.
Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by mutations in the AGXT gene, leading to impaired glyoxylate metabolism and excessive oxalate accumulation, resulting in nephrolithiasis, nephrocalcinosis, and end-stage renal disease. As a rare and often neglected disease, PH1 poses a significant challenge to modern healthcare systems due to its progressive nature and limited therapeutic options. In this study, an integrated in silico approach was employed to identify pathogenic single-nucleotide polymorphisms (SNPs) and evaluate potential therapeutic candidates. Computational analyses using ConSurf, Align-GVGD, INPS-MD, CUPSAT, and iStable identified G161C and Y260C as highly deleterious variants affecting protein stability. Virtual screening, followed by ADME and toxicity assessments, identified Tauroursodeoxycholic acid (TUDCA) as a promising candidate with favorable pharmacokinetic and safety profiles. Molecular docking revealed that TUDCA exhibited higher binding affinity than the reference drug pyridoxine across native and SNP variants of AGXT proteins. Molecular dynamics simulations (300 ns) demonstrated enhanced structural stability of TUDCA-bound complexes, indicated by reduced RMSD and RMSF, improved compactness, and sustained hydrogen bonding. Furthermore, free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) analyses confirmed improved conformational stability and coordinated residue motions in SNP variant structures. Overall, these findings suggest that TUDCA may effectively stabilize structural alterations induced by pathogenic AGXT variants, highlighting its potential as a precision medicine-based therapeutic strategy for PH1.
2026-01-02 | Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase (AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase (GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate metabolism, have shown promise in reducing oxalate burden. However, recently approved siRNA therapies remain limited by high cost, unfavorable pharmacokinetics, and limited global accessibility. We report the development of compound 2, a dual GO/LDHA inhibitor (Ki = 390 and 40 nM, respectively) that also promotes hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy was evaluated in Agxt-/- mice, both in primary hepatocytes and through oral administration. Treatment significantly reduced hepatic LDHA levels, urinary oxalate excretion, and renal calcium-oxalate crystal deposition. These findings support compound 2 as a first-in-class, orally bioavailable small molecule with dual inhibitory and proteolytic activity, offering a novel therapeutic candidate for PH1 and other oxalate-related pathologies.
2025-09-11 | Primary Hyperoxaluria Type 1: An Unexpected Diagnosis after Kidney Transplantation.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by a deficiency of the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase, which catalyzes the conversion of glyoxylate to glycine, resulting in increased oxalate production. The clinical consequences of the progressive buildup of oxalates include nephrocalcinosis, nephrolithiasis, chronic kidney disease, and ultimately, renal failure with extra-renal involvement. The diagnosis of PH1 is challenging due to the non-specific nature of its symptoms and the need for costly genetic testing. For many years, the management of PH1 was mainly supportive care. Currently, we have access to novel RNA interference (RNAi) therapeutics, such as lumasiran and nedosiran, which reduce hepatic oxalate production; however, they are prohibitively expensive in most countries. The only curative treatment is liver transplantation, and in cases that progress to end-stage kidney disease (ESKD), simultaneous dual kidney and liver transplantation is usually indicated. We present a case of a 46-year-old woman admitted to our clinic on the eighth day of post-kidney transplantation for evaluating the causes of delayed graft function. During the diagnostic work-up, PH1 was diagnosed. A biopsy of the transplanted kidney also revealed microvascular inflammation (MVI). The patient was treated with fluid therapy, a restrictive diet, pyridoxine, and initially, intensive hemodialysis. Given the identification of a genetic variant of the disease that responds well to pyridoxine treatment, and considering the exceedingly high cost of lumasiran therapy, this medication was not utilized. In addition, it was decided to administer methylprednisolone pulses, plasmapheresis, and immunoglobulin infusions in response to MVI. This treatment resulted in improvements in both clinical and laboratory parameters. PH1 is a rare cause of calcium oxalate nephrolithiasis and nephrocalcinosis and should be considered in the differential diagnosis of patients with progressive renal failure. This case highlights the importance of early diagnosis, which allows optimal supportive and/or RNAi therapy and appropriate qualification for kidney transplantation in cases of ESKD. This is particularly important as isolated kidney transplantation (without concomitant liver transplantation) can lead to rapid loss of graft function and may ultimately prove futile.
cell therapies
2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2026-01-13 | Don’t think that combined liver–kidney transplant can solve everything in primary hyperoxaluria type 1!
Sandrine Lemoine, Anne-Laure Sellier-Leclerc, Alice Koenig, Charlène Levi, Justine Bacchetta; Don’t think that combined liver kidney transplant can solve e
2025-12-15 | Combined liver and kidney transplantation: Experience and outcomes at Baskent university
Introduction Combined liver and kidney transplantation (CLKT) is a complex but essential procedure in selected patients with dual organ failure. We present our single-center experience with CLKT in children and adults. Materials and Methods We retrospectively analyzed 11 patients who underwent CLKT at our center between 1988 and 2024 regarding demographic and clinical data, including age, sex, transplant type (simultaneous/sequential), etiology, dialysis status, graft/patient survival, rejection, and oxalate levels. We also evaluated lymphocyte cross-match, panel reactive antibody screening, and complement-dependent cytotoxicity testing. Results Patients included 7 female and 4 male patients (mean age 18 years); 8 were pediatric and 3 were adult recipients. One patient with primary hyperoxaluria underwent a simultaneous liver-kidney transplant, and 10 patients received sequential transplants. Six patients were diagnosed with primary hyperoxaluria. The patient with simultaneous deceased donor transplant experienced early graft loss due to oxalate deposition and humoral rejection. Four patients experienced kidney graft rejection (1 cellular, 3 humoral). One patient with cryptogenic cirrhosis and persistent hepatorenal syndrome died from sepsis in the early postoperative period. A patient with progressive familial intrahepatic cholestasis later developed focal segmental glomerulosclerosis, which was potentially related to long-term tacrolimus exposure. Another patient required graft nephrectomy following thrombotic microangiopathy. The remaining 8 patients had favorable long-term outcomes without significant complications. Conclusions Our experience supports the staged transplant approach for hyperoxaluria and highlights the importance of individualized immunosuppressive strategies. Renal grafts were more susceptible, underscoring the need for vigilant immunologic assessment. Further multicenter studies are warranted to optimize transplant timing and improve outcomes in this complex patient population.
2024-09-01 | 364.13: Life-saving liver transplant procedure for pediatric and adult patients: Domino liver transplantation.
Introduction: Organ shortages made it clear that liver transplantation (LT) alone was an inadequate method. Domino liver transplantation (DLT) is the use of an explanted liver from patients with a limited number of liver diseases, such as metabolic enzyme defect, as a graft for other suitable patients. DLT can be a important option for patients with low chances on the waiting list and who do not have a suitable donor to live a healthy life. In this study, we presented three DLT and their results. Method: Case-1: First patient was a 12-year-old girl with primary hyperoxaluria type-1 (PH1). Liver function tests and liver biopsy was normal. We performed left lobe LT from his mother and transplanted the liver, which was obtained from this girl with PH-1, to another 55-year-old patient with cryptogenic liver cirrhosis and hepatocellular carcinoma (HCC). Both patients were successfully discharged. Case-2: The patient was a 5-year-old boy and was diagnosed with propionic acidemia (PA). He had epilectic discharges and had to eat a protein-restricted diet. Liver function tests and biopsy were normal. We performed left lobe LT from his mother. We transplanted the liver we obtained from the patient with PA to our 6-year-old girl, who we transplanted liver for metabolic liver disease from her father 2 years ago but is currently in the process of chronic rejection. The recipients were discharged on postoperative day 8. Case-3: A 2-year-old patient with mapple syrup urine disease (MSUD) underwent left lateral lobe LT from his father. Since the patient’s liver function tests were normal and the biopsy was normal, we transplanted the liver graft obtained from the patient to a 6-year-old boy with familial hypercholesterolemia. Both patients were successfully discharged on postoperative day 9. Results: The patient with PH1 underwent kidney transplantation (KT) 1 month after LT. Eight months after KT, serum creatinine value was 0.8 mg/dL and there was no evidence of oxalate calculi in radiologic evaluations. The total bilirubin (T.bil) level of the patient diagnosed with HCC decreased from 3.7 mg/dl to 0.8 mg/dl in the first month after LT. Patients with PA and MSUD were not subjected to any dietary restriction after LT. In addition, no neurologic complications such as seizures were observed after LT. T.bil level of the patient diagnosed with metabolic liver disease after LT decreased from 26.7 mg/dl to 0.8 mg/dl in the 4th postoperative month. The total cholesterol value of the patient with familial hypercholesterolemia decreased from 755 mg/dl to 263 mg/dl on postoperative day 8. Conclusion: Domino LT, if performed carefully by selecting the right patients with the right indications, can be an important graft source for patients who do not have a suitable donor and are on the waiting list for liver transplantation.
2024-04-05 | Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the AGXT gene. Combined liver and kidney transplantation is currently the only permanent curative treatment. We combined locus-specific gene correction and hepatic direct cell reprogramming to generate autologous healthy induced hepatocytes (iHeps) from PH1 patient-derived fibroblasts. First, site-specific AGXT corrected cells were obtained by homology directed repair (HDR) assisted by CRISPR-Cas9, following two different strategies: accurate point mutation (c.731T>C) correction or knockin of an enhanced version of AGXT cDNA. Then, iHeps were generated, by overexpression of hepatic transcription factors. Generated AGXT-corrected iHeps showed hepatic gene expression profile and exhibited in vitro reversion of oxalate accumulation compared to non-edited PH1-derived iHeps. This strategy set up a potential alternative cellular source for liver cell replacement therapy and a personalized PH1 in vitro disease model.
proteins
2026-04-14 | Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.
Phosphorylation is a fundamental post-translational modification that contributes to the dynamic control of protein function and stability. More than 300,000 site-specific phosphorylation sites have been detected across > 20,000 human proteins, yet only a small fraction (~ 5%) have been experimentally characterized, and their roles in health and disease remain largely unexplored. In particular, the functional consequences of most phosphorylation events in metabolic enzymes remain unknown. Here, we investigated the functional impact of modifying Ser81 in alanine:glyoxylate aminotransferase (AGT), the key enzyme responsible for glyoxylate detoxification and whose loss-of-function causes Primary Hyperoxaluria Type I (PH1). We examined phosphomimetic substitutions at Ser81 in the WT (wild-type) enzyme, the common polymorphic minor allele (LM, containing two variations, p.P11L and p.I340M), and the two most frequent PH1-associated variants (LM-p.G170R and LM-p.I244T). Using biochemical, biophysical and cell-based approaches, we found that introducing a negative charge at Ser81 (through the S81D substitution) strongly perturbs PLP (pyridoxal 5´-phosphate)/PMP (pyridoxamine 5´-phosphate) binding pose and disrupts catalytic activity, while preserving secondary and tertiary structure as well as peroxisomal localization. In contrast, the non-charged S81A substitution produced milder effects. These results indicate that Ser81 contributes to stabilizing the cofactor interaction network at the AGT active site. Our findings therefore identify Ser81 as a previously uncharacterized regulatory position that can critically influence AGT activity. Although further work is required to determine the physiological frequency and regulatory context of this modification in vivo, our results suggest that phosphorylation at this position could represent an additional modulatory layer influencing AGT function and genotype-phenotype relationships in PH1, with potential implications for understanding regulatory mechanisms affecting AGT activity in disease.
2022-12-01 | Oxalate Chelating Activity of Egg White Proteins and Their Hydrolysates
Major egg white proteins and their hydrolysates serve as functional food ingredients that have certain metal-chelating properties. Employing egg white proteins and their hydrolysates to scavenge dietary oxalates is anticipated to have beneficial effect in the prevention of kidney stones. The objective of this study was to determine the biogenic oxalate-chelating activity of ovalbumin, ovomucin, and ovotransferrin and their hydrolysates. To prepare oxalate extracts, 30 mL of 0.25 N HCl was added to separately to 0.5 g of dried spinach and starfruit powders followed by boiling for 15 min, and after cooling, the addition of a further 20 mL of 0.25 N HCl. Having prepared these extracts, ovalbumin, ovomucin, and ovotransferrin and their hydrolysates were separately mixed with oxalate extracts and incubated at 3°C for 24 h. Following centrifugation, supernatants were analyzed by HPLC using a reverse-phase C18 column coupled with a diode array detector. We found that all assessed proteins and their hydrolysates showed biogenic oxalate-chelating activity against the oxalates of spinach. In contrast, however, only ovalbumin, ovalbumin-hydrolysate, and ovomucin showed chelating activity (57.10%±8.84%, 85.44%±5.30%, 73.20%±4.13%, respectively) against the oxalates of starfruit (P<0.05). Overall, hydrolyzed ovalbumin was identified as the most effective chelator of the oxalates both spinach and starfruit. In this study, we thus established that the assessed egg white proteins and their hydrolysates have oxalate-chelating activity in vitro, thereby indicating that these compounds have potential utility as nutraceuticals for the chelation of dietary oxalate. However, further research will be necessary to verify their oxalate-chelating activities against different fruits and vegetables and under specific in vivo conditions and against purified oxalate.
2021-11-25 | Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria Type 1 and end-stage renal disease: a Phase II study.
In primary hyperoxaluria Type 1 (PH1), endogenous oxalate overproduction significantly elevates urinary oxalate excretion, resulting in recurrent urolithiasis and/or progressive nephrocalcinosis and often early end-stage renal disease (ESRD). In ESRD, dialysis cannot sufficiently remove oxalate; plasma oxalate (Pox) increases markedly, inducing systemic oxalate deposition (oxalosis) and often death. Interventions to reduce Pox in PH1 subjects with ESRD could have significant clinical impact. This ongoing Phase II, open-label trial aimed to evaluate whether long-term Oxabact™ (Oxalobacter formigenes, OC5, OxThera Intellectual Property AB, Sweden) lowers Pox in PH1 ESRD subjects, ameliorating clinical outcome. PH1 ESRD subjects on stable dialysis regimens were examined. Subjects were administered one OC5 capsule twice daily for up to 36 months or until transplantation. Total Pox values, cardiac function and safety were evaluated. Free Pox was evaluated in a comparative non-treated PH1 dialysis group using retrospective chart reviews and analyses. Twelve subjects enrolled in an initial 6-week treatment phase. Following a washout of up to 4 weeks, eight subjects entered a continuation study; outcomes after 24 months of treatment are presented. After 24 months, all subjects had reduced or non-elevated Pox compared with baseline. Cardiac function improved, then stabilized. No treatment-related serious adverse events were reported. Compared with an untreated natural control cohort, 24 months OC5 administration was beneficial to PH1 ESRD subjects by substantially decreasing Pox concentrations, and improving or stabilizing cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated.
2020-10-01 | Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys
Short bowel (SB) increases the risk of kidney stones. However, the underlying mechanism is unclear. Here, we examined how SB affected renal oxalate and citrate handlings for in vivo hyperoxaluric rats and in vitro tubular cells. SB was induced by small intestine resection in male Wistar rats. Sham-operated controls had no resection. After 7 days of recovery, the rats were divided into control, SB (both fed with distilled water), ethylene glycol (EG), and SB+EG (both fed with 0.75% EG for hyperoxaluric induction) groups for 28 days. We collected the plasma, 24 h of urine, kidney, and intestine tissues for analysis. Hypocitraturia was found and persisted up to 28 days for the SB group. Hypocalcemia and high plasma parathyroid hormone (PTH) levels were found in the 28-day SB rats. SB aggravated EG-mediated oxalate nephropathy by fostering hyperoxaluria and hypocitraturia, and increasing the degree of supersaturation and calcium oxalate (CaOx) crystal deposition. These effects were associated with renal up-regulations of the oxalate transporter solute carrier family 26 (Slc26)a6 and citrate transporter sodium-dependent dicarboxylate cotransporter-1 (NaDC-1) but not Slc26a2. The effects of PTH on the SB kidneys were then examined in NRK-52E tubular cells. Recombinant PTH attenuated oxalate-mediated cell injury and up-regulated NaDC-1 via protein kinase A (PKA) activation. PTH, however, showed no additive effects on oxalate-induced Slc26a6 and NaDC-1 up-regulation. Together, these results demonstrated that renal NaDC-1 upregulation-induced hypocitraturia weakened the defense against Slc26a6-mediated hyperoxaluria in SB kidneys for excess CaOx crystal formation. Increased tubular NaDC-1 expression caused by SB relied on PTH.
2019-06-14 | Induction of enteric oxalate secretion by Oxalobacter formigenes in mice does not require the presence of either apical oxalate transport proteins Slc26A3 or Slc26A6
Oxalobacter sp. promotion of enteric oxalate excretion, correlating with reductions in urinary oxalate excretion, was previously reported in rats and mice, but the mechanistic basis for this affect has not been described. The main objective of the present study was to determine whether the apical oxalate transport proteins, PAT1 (slc26a6) and DRA (slc26a3), are involved in mediating the Oxalobacter-induced net secretory flux across colonized mouse cecum and distal colon. We measured unidirectional and net fluxes of oxalate across tissues removed from colonized PAT1 and DRA knockout (KO) mice and also across two double knockout (dKO) mouse models with primary hyperoxaluria, type 1 (i.e., deficient in alanine-glyoxylate aminotransferase; AGT KO), including PAT1/AGT dKO and DRA/AGT dKO mice compared to non-colonized mice. In addition, urinary oxalate excretion was measured before and after the colonization procedure. The results demonstrate that Oxalobacter can induce enteric oxalate excretion in the absence of either apical oxalate transporter and urinary oxalate excretion was reduced in all colonized genotypes fed a 1.5% oxalate-supplemented diet. We conclude that there are other, as yet unidentified, oxalate transporters involved in mediating the directional changes in oxalate transport across the Oxalobacter-colonized mouse large intestine.
oligonucleotides
2026-08-01 | A Case Report of Primary Hyperoxaluria Type 1 Diagnosed in a Geriatric Patient on Dialysis: Unique Clinical Course With Lumasiran
Primary hyperoxaluria (PH) is a group of rare autosomal recessive disorders of impaired hepatic glyoxylate metabolism. Primary hyperoxaluria type 1 (PH1), the most common and severe phenotype, results in incident kidney failure in most patients by young adulthood (1). The majority of PH1 patients are diagnosed around age 10 years, though a significant delay in diagnosis is common (2). Preventative treatment options have historically been limited to robust fluid intake, crystallization inhibitors, and pyridoxine.
2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
2026-05-04 | Isolated Kidney Transplant in Primary Hyperoxaluria-1 Enabled by Small Interfering RNA (siRNA) Therapy. Is It Time for Change? Case Report and Review of the Literature.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production that leads to nephrocalcinosis or nephrolithiasis and progressive kidney failure, associated with systemic oxalosis that is not reversed by dialysis. Pharmacological treatment is limited. Combined or sequential liver and kidney transplant is standard of care for PH1. Recently approved RNA-interference (RNAi) therapy with lumasiran or nedosiran targeting glycolate oxidase and lactate dehydrogenase A, respectively, reduces hepatic oxalate synthesis. This makes kidney-only (isolated) transplantation (iKT) a potentially successful, novel approach for managing PH1 patients with advanced kidney disease combined with hyperhydration, urine alkalinization, and vitamin B6 (where applicable). We analyzed the course of a young PH1 kidney transplant recipient at our institution and performed a literature review of patients with small interfering RNA-enabled iKT. A patient with PH1 due to a homozygous, pathogenic variant in AGXT exon 1 (c.121G>A; p.Gly41Arg) received a deceased donor kidney transplant after 6.5 years of hemodialysis and 4.3 years of RNAi therapy with lumasiran. He maintained good kidney allograft function 9 months post-transplant despite the occurrence of an asymptomatic calyceal stone within the graft prior to transition to adult nephrology care. At 14 months, he experienced a T cell-mediated rejection, associated with a rise in serum creatinine and plasma oxalate, and a partially obstructing stone. A review of all 10 accessible cases of RNAi-supported iKT, including our own, revealed several instances of kidney stone formation (20%), stent obstruction (20%), and mild, mostly transient crystal deposition in the graft (37.5%). This report enriches the limited experience of RNAi-enabled kidney-only transplantation in PH1. RNA interference therapy has the potential to challenge the current standard of dual liver and kidney transplantation in children and young adults with this devastating disease but requires uninterrupted access to the drug with individualized, eGFR and oxalate level adjusted dosing, continued vigilance, and reporting of long-term outcomes.
2026-05-01 | Rescue of Renal Function After Novel RNA Interference Therapy (Lumasiran) for Catastrophic Post–Kidney Transplant Recurrent Oxalate Nephropathy in Primary Hyperoxaluria Type 1
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive genetic disorder of hepatic glyoxylate metabolism leading to overproduction of oxalate commonly resulting in nephrocalcinosis, renal failure and subsequent systemic oxalosis. The advent of small interfering RNA (siRNA) therapies such as lumasiran and nedosiran could represent a paradigm shift in the management of PH1 and may avoid the need for liver transplantation in some. However, to date, limited evidence on the management of patients exists when the diagnosis of PH1 is made only after renal transplantation. This report details a case of late diagnosis of PH1 in a 23-year-old adult who only received the diagnosis after renal transplantation and subsequent declining graft function. Missed opportunities for genetic testing included no investigation of echogenic kidneys on ultrasound at presentation, and no consideration of the diagnosis at the first transplant biopsy despite oxalate deposition. Genotyping revealed a pyridoxine-resistant phenotype and the patient's transplant function was stabilised by the use of lumasiran. To our knowledge, this case represents the first time lumasiran has been reported as a salvage therapy in an adult patient who was only diagnosed with PH1 following renal transplantation. This case highlights the importance of genetic testing in young patients with otherwise unexplained renal disease and should inform future guidelines regarding salvage therapy in adult patients who receive a late diagnosis.
2026-04-28 | Late Diagnosis of Primary Hyperoxaluria Type 1 After Kidney Transplant
Primary hyperoxaluria type 1 is a rare and often unrecognized cause of renal allograft dysfunction and loss, particularly when renal disease is attributed to recurrent nephrolithiasis. We report the case of a 62-year-old woman with a history of bilateral nephrolithiasis and prolonged use of anti-inflammatory drugs who underwent kidney transplantation with immediate graft function and an initially favorable course. After an extended period of stability, late and progressive graft dysfunction occurred. Allograft biopsy demonstrated tubular injury associated with extensive calcium oxalate crystal deposition, suggesting oxalosis. Serum oxalate was 18.6 µmol/L, and urinary oxalate was 94.9 mg/24 h. Genotyping identified a homozygous pathogenic variant in the AGXT gene, confirming the diagnosis of primary hyperoxaluria type 1. Review of the medical history revealed nephrocalcinosis in native kidneys, and family screening identified a sibling with nephrolithiasis. Pharmacological-dose pyridoxine was initiated as first-line therapy based on the responsive genotype, followed by RNA interference therapy with lumasiran due to the high risk of graft loss, resulting in initial stabilization of graft function. This report emphasizes that primary hyperoxaluria type 1 should be considered in transplant recipients with a history of nephrolithiasis, even in adulthood, and that post-transplant identification has direct implications for graft prognosis, therapeutic approach, and family screening, highlighting the need for metabolic and genetic investigation in selected cases before transplantation.
other
2026-09-22 | Adeno-Associated Viral Vector (AAV)-Mediated In Vivo CRISPR-Cas9 Delivery.
CRISPR-based gene editing is a growing therapeutic strategy for modifying or silencing disease-causing genes. This chapter focuses on the in vivo delivery of CRISPR systems using recombinant adeno-associated viral (rAAV) vectors. Specifically, we detail a methodology using a rAAV vector carrying Staphylococcus aureus Cas9 (SaCas9) to target the murine Hao1 gene in liver parenchymal cells as a curative treatment for primary hyperoxaluria type 1 (PH1). We provide comprehensive protocols for plasmid design and cloning, rAAV production, animal administration, and evaluation of editing efficacy.
2026-06-16 | In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.
2026-04-13 | Novel AAV843 Vector-Mediated Gene Replacement Therapy Rescues Primary Hyperoxaluria Type I in Mice.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder resulting from mutations in the alanine-glyoxylate aminotransferase (AGXT) gene, leading to excessive systemic deposition of calcium oxalate. This condition is an important cause of end-stage renal disease in children and poses a serious threat to patient survival. Current therapeutic approaches are limited primarily to conservative management and organ transplantation, underscoring the need for more effective treatments. Gene replacement therapy represents a promising alternative strategy. In this study, Agxt-/- mice lacking exons 3-8 were characterized, confirming the complete loss of hepatic alanine-glyoxylate aminotransferase (AGT) expression and the presence of early-onset hyperoxaluria. Exposure to glyoxylic acid induced pronounced renal calcium oxalate crystal deposition, establishing a robust and previously unreported induction approach in gene-edited PH1 mouse models. Using this platform, human AGXT cDNA was delivered via the liver-tropic, low-immunogenic AAV843 vector, which has been employed in clinical trials for hemophilia. Gene therapy resulted in normalization of urinary oxalate levels, restoration of hepatic AGT expression, and significant attenuation of renal injury and nephrocalcinosis. These therapeutic effects were accompanied by significant suppression of key mediators involved in renal inflammation, necroptosis, and fibrosis. Moreover, transgene expression was highly specific to the liver and was not associated with hepatotoxicity. These results demonstrate that AAV843-mediated AGXT gene replacement is a safe and effective approach that achieves phenotypic correction in a murine model of PH1, warranting further evaluation in preclinical studies.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-12-03 | Genetic Correction of the Most Common Mutation Causing Primary Hyperoxaluria Restores Enzyme Localization and Oxalate Metabolism.
Our research aimed to model primary hyperoxaluria type 1 in vitro using a stem cell model and assess the potential of adenine base editors in correcting the most common pathogenic AGXT genetic variant, c.508G>A (Gly170Arg), which leads to oxalate accumulation due to alanine-glyoxylate aminotransferase mislocalization. Patient-derived fibroblasts were induced to pluripotent stem cells, genetically corrected with adenine base editing, and subsequently differentiated into hepatocyte-like cells in parallel with their non-corrected isogenic counterparts. Enzyme localization was assessed through immunocytochemistry and confocal microscopy. The key metabolites associated with the disease were analyzed using liquid chromatography-mass spectrometry to evaluate the metabolic phenotype. Finally, lipid nanoparticle formulations were designed and tested as an in vivo-applicable delivery method for base editors. All induced pluripotent stem cell lines successfully differentiated into hepatocyte-like cells and expressed essential hepatocyte markers, including ALB, HNF1A, and AGXT. Adenine base editor-mediated genetic correction of the pathogenic AGXT mutation restored enzyme localization into peroxisomes and diminished oxalate accumulation without significant off-target effects. Base editor mRNA and AGXT variant targeting single guide RNA encapsulated within lipid nanoparticles mediated gene correction in the hepatocyte-like cell model. Using an in vitro model of primary hyperoxaluria type 1, we showed that base editor-mediated genetic correction of the most common hyperoxaluria-causing variant corrects enzyme mislocalization from mitochondria to peroxisomes and improves metabolic function. These results propose gene correction as a potential therapeutic approach to hyperoxaluria.
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Drug Discovery Landscape
6 orphan drug designations for Primary hyperoxaluria type 1, including 1 approved therapy.
6 orphan drug designations for Primary hyperoxaluria type 1, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
5-[[trans-4-[(trifluoromethoxy)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylic acid | small molecules | FDA | — | BioMarin Pharmaceutical Inc. |
Bacillus subtilis oxalate decarboxylase | proteins | FDA | Allena Pharmaceuticals, Inc. | |
lumasiran [Oxlumo] | RNAs | FDA | Approved | Alnylam Pharmaceuticals |
Synthetic double-stranded RNA oligonucleotide specific to hydroxyacid oxidase 1 gene [DCR-PH1] | RNAs | EMA | [INACTIVE] Dicerna EU Limited | |
synthetic double-stranded (hybridized duplex) ribonucleic acid oligonucleotide specific to hydroxyacid oxidase 1 gene | RNAs | FDA | Dicerna Pharmaceuticals, Inc. | |
Adeno-associated viral vector serotype 5 containing the human AGXT gene | gene therapies | EMA | — | uniQure Biopharma B.V |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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