RARE DISEASE
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria
Synonyms: CEP, Günther disease
Synonyms: CEP, Günther disease
Synonyms: CEP, Günther disease
Drug discovery
3
drugs
With orphan designations
Overview
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder caused by uroporphyrinogen III synthase (UROS) deficiency, leading to toxic accumulation of type I porphyrins. Clinical features include severe photosensitivity with blistering skin lesions, erythrodontia, hemolytic anemia, splenomegaly, and potential skeletal abnormalities. Diagnosis involves elevated uroporphyrin I in urine/erythrocytes and genetic confirmation. Management focuses on photoprotection, hematologic support, and advanced therapies like hematopoietic stem cell transplantation [1][4][6][10].
Burden
High morbidity: Photomutilation, chronic anemia, infections, and osteolytic complications [4][6][10]
Reduced life expectancy (median 40-60 years) in severe cases, with significant psychosocial impacts [7][11][14]
Requires multidisciplinary care (dermatology, hematology, genetics) and lifelong monitoring [6][10][16]
Therapies
First-line: Strict sunlight avoidance, protective clothing/window films [4][14]
Hematologic: Transfusions, splenectomy, hydroxyurea; hematopoietic stem cell transplantation for severe cases [8][9][13]
Emerging: Proteasome inhibitors (bortezomib), gene therapy, and iron depletion via phlebotomy/deferasirox [3][13][19]
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
140 drug discovery papers about Congenital erythropoietic porphyria, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
140 drug discovery papers about Congenital erythropoietic porphyria, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-03-04 | Congenital erythropoietic porphyria: the overlooked inherited disorder.
Congenital erythropoietic porphyria (CEP) also known as Gunther's disease is a subtype of porphyria. It is an autosomal recessive disorder caused by a mutation in the uroporphyrinogen III gene (URO III) coding for the enzyme UROS synthase, an essential enzyme in the heme synthesis pathway. The condition may present as non-immune hydrops in foetuses, dark-red urine-stained diapers in neonates and skin blistering and mutilation in sun-exposed areas in older children. Enzyme assays and genetic studies are costly and not easily available in low-resource settings; therefore, awareness of the typical phenotype of this rare porphyria is crucial. However, due to the scarcity of reported cases, clinicians remain oblivious to the disease, leading to delays in diagnosis and initiation of treatment, thus contributing to long-term disabilities. We report a case of a male child in early adolescence presenting with classical cutaneous, skeletal and haematological features of CEP.
1970-09-01 | Congenital Erythropoietic Porphyria. II. The Effects of Induced Polycythemia
Abstract Polycythemia and anemia were induced in a patient with congenital erythropoietic porphyria as a possible means of altering erythropoiesis and its attendant porphyrin production. Maintenance of hematocrits at 50 per cent and 60 per cent for periods of 2 weeks decreased both erythropoiesis and porphyrin excretion to about one-half of their initial levels. Conversely with a hematocrit of 25, erythropoiesis and porphyrin production were increased to about twice the basal level. Examination of the marrow showed fluorescence in all late normoblasts and indicated that the patient has only one red cell population. During induced polycythemia, a shift in marrow erythroid population to relatively mature forms, apparently related to delayed enucleation, was accompanied by a retention of the reticulocyte pool and fluorescent cells within the marrow. During anemia, the occurrence of relatively more immature erythroid cells was accompanied by a shift of the reticulocyte pool and fluorescent cells into the circulating blood. During polycythemia, increases were observed in the relative number of nuclear vacuoles peculiar to this disease, in the retention of radioiron in the marrow and in the relative amount of stercobilin excretion. In anemia these parameters decreased towards normal.
1968-03-01 | Determination of a Skin-Related Erythropoietic Substance
SummaryA method is presented for the extraction of a hemin-stimulated, heat stable erythropoietically active fraction (HSP) from the skin of subcutaneously injected animals. The production of HSP is not species specific; similar substances were produced by the enderonic tissues of the cat, guinea pig, rabbit, rat, and mouse. While the production of HSP is coincident with inflammation produced by hemin injection, the production is not inflammation-dependent per se since other inflammatory substances tested do not stimulate production. The HSP compares favorably with erythropoietin Standard B (from human urine) for erythropoietic activity in the fasting “dehydrated” rat. Its activity has also been confirmed in the polycythemic rat. The dose-response curve for HSP administration shows a definite response to as little as 70 μg. The maximal response plateaus at a dose of about 1 mg.
cell therapies
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2025-02-11 | Scavenger endothelial cells alleviate tissue damage by engulfing toxic molecules derived from hemolysis.
Hemolysis induces tissue damage by releasing cellular contents into the plasma. It is widely accepted that hemolysis-derived toxic molecules are cleared by macrophages or metabolized in hepatocytes. In zebrafish, we found that scavenger endothelial cells (SECs), a specialized endothelium with remarkable endocytosis capability, engulf both macromolecular hemoglobin (Hb) and small molecular unconjugated bilirubin (UCB), two primary toxic byproducts of hemolysis. These engulfment processes are mediated by the scavenger receptor Stab2. To demonstrate the protective function of SECs during hemolysis, we employed a zebrafish model of erythropoietic porphyria, characterized by excessive protoporphyrin IX (PPIX) accumulation due to ferrochelatase mutation, leading to light-sensitive hemolysis and larva death. We found that SECs facilitate the clearance of excess PPIX via Stab2, thereby mitigating PPIX-induced larval mortality. In addition, mouse SECs possess a conserved capability of scavenging Hb/UCB/PPIX. In conclusion, our study identifies SECs as a detoxification system during physiological and pathological hemolysis, shedding light on their protective role against hemolysis-induced damage.
2024-01-30 | VERY EARLY DIAGNOSIS AND MANAGEMENT OF CONGENITAL ERYTHROPOIETIC PORPHYRIA AT BIRTH
Congenital erythropoietic porphyria (CEP) is caused by a defect in the heme biosynthesis pathway of the enzyme uroporphyrinogen III synthase (UROS) leading to an accumulation of non-physiological porphyrins. The exposure of accumulated porphyrins to sunlight causes severe photosensitivity, chronic intravascular hemolysis and, eventually, irreversible mutilating deformities. Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusion, hydroxyurea and splenectomy are commonly used in the management of CEP. Currently, the only available curative treatment of CEP is HSCT. We present a child with a very early diagnosis of CEP, who became the youngest successful HSCT for CEP.
2024-01-27 | Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: A case report
Abstract Congenital erythropoietic porphyria (CEP), or Gunther disease, is a rare genetic disease responsible for severe dermatologic, hepatic and/or haematological damages related to the deficient activity of the uroporphyrinogen III synthase. Allogeneic stem cell transplantation (Allo‐SCT) represents the only curative treatment and few allotransplanted cases have been reported in children but not in adults. Here we report for the first time the successful cure of a 46‐year old man with CEP with a 5‐year follow‐up after Allo‐SCT.
2024-01-23 | Severe Perinatal Presentations of Günther's Disease: Series of 20 Cases and Perspectives.
(1) Background: Congenital erythropoietic porphyria (CEP), named Günther's disease, is a rare recessive type of porphyria, resulting from deficient uroporphyrinogen III synthase (UROS), the fourth enzyme of heme biosynthesis. The phenotype ranges from extremely severe perinatal onset, with life-threatening hemolytic anaemia, to mild or moderate cutaneous involvement in late-onset forms. This work reviewed the perinatal CEP cases recorded in France in order to analyse their various presentations and evolution. (2) Methods: Clinical and biological data were retrospectively collected through medical and published records. (3) Results: Twenty CEP cases, who presented with severe manifestations during perinatal period, were classified according to the main course of the disease: antenatal features, acute neonatal distress and postnatal diagnosis. Antenatal symptoms (seven patients) were mainly hydrops fetalis, hepatosplenomegaly, anemia, and malformations. Six of them died prematurely. Five babies showed acute neonatal distress, associated with severe anemia, thrombocytopenia, hepatosplenomegaly, liver dysfunction, and marked photosensitivity leading to diagnosis. The only two neonates who survived underwent hematopoietic stem cell transplantation (HSCT). Common features in post-natal diagnosis (eight patients) included hemolytic anemia, splenomegaly, skin sensitivity, and discoloured teeth and urine. All patients underwent HSCT, with success for six of them, but with fatal complications in two patients. The frequency of the missense variant named C73R is striking in antenatal and neonatal presentations, with 9/12 and 7/8 independent alleles, respectively. (4) Conclusions: The most recent cases in this series are remarkable, as they had a less fatal outcome than expected. Regular transfusions from the intrauterine period and early access to HSCT are the main objectives.
small molecules
2025-12-31 | Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
2025-12-30 | New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide. We identified pharmacotherapies (leaving out, for example, topical applications such as sunscreens or supplements such as iron) which are currently (that is, within the last 5 years) evaluated for EPP from clinical trial registries and investigated whether the trial designs allow a comparison of their treatment effects with each other and with afamelanotide. Therefore, we analysed the clinical trial protocols with emphasis on their trial designs, efficacy outcome measures, inclusion and exclusion criteria, safety aspects and, if available, published results. Our search in the clinical trials registries retrieved 29 trials that included patients with EPP. From these, we identified 16 clinical trials evaluating afamelanotide and three new pharmacotherapies, i.e., dersimelagon, bitopertin and cimetidine. Safety and efficacy of all new pharmacotherapies are currently being investigated against placebo-control groups or against baseline. Because of differences in the outcome measures and included patient populations, the results of the trials cannot be directly compared. Moreover, methodically challenging aspects and ethical issues were identified in some of the trial protocols. Efficacy and safety of currently investigated treatments for EPP are not directly comparable. We wrote this manuscript as a call to action to Principal Investigators, Ethical Review Boards, Regulatory Authorities and the sponsors of trials because we are convinced that trials directly assessing new pharmacotherapies against afamelanotide would be the more informative, and methodological and ethically sounder trial design. Not applicable. The online version contains supplementary material available at 10.1186/s13023-025-04170-9.
2024-11-05 | Uncoupling Alas2 from Iron-Regulatory Proteins Demonstrates the Protective Role of Alas2 Iron-Responsive Element in Protoporphyrias
Introduction. Many genes relevant to iron metabolism include a transcribed cis-regulatory element called iron-responsive element (IRE) that couples their expression to the availability of intracellular iron. Canonical IREs consist of a conserved stem-loop structure in the 5‘ or 3‘ untranslated region (UTR) of these mRNAs. IREs are bound by two iron-regulatory proteins (IRP1 & IRP2) to either limit the translation of the targeted transcript or to stabilize it. Among the 5'UTR IRE- genes, ALAS2, the erythroid-specific aminolevulinate synthase, catalyzes the first step of heme biosynthesis. Loss-of-function and gain-of-function mutations cause X-linked Sideroblastic Anemia (XLSA) and X-linked Protoporphyria (XLPP). A deficiency in the last enzyme of the pathway, ferrochelatase (FECH), causes the most common Erythropoietic Protoporphyria (EPP). A single-family with protoporphyria has been described with a mutation in the mitochondrial unfoldase CLPX. In the mouse, targeted deletion of IRP2 also results in protoporphyria. Several lines of evidence suggest a role for Alas2 in modifying the severity of erythroid porphyrias. In 4 patients with congenital erythropoietic porphyria due to the same UROS genotype, an XLPP mutation was also found in the most severely affected individual. A mutation in the Alas2-IRE has been described as a modifier in the CLPX-family. Furthermore, increased levels of Alas2 mRNA have been reported in EPP patients. Lastly, other reports suggest that iron deficiency may be protective in protoporphyrias. Methods. We generated a mouse line lacking the loop of Alas2-IRE (Alas2ΔLOOP), which should uncouple ALAS2 expression from IRP-dependent regulation. We phenotyped hemizygous male Alas2ΔLOOP/Y mice from 1 to 8 weeks of age. We compared their phenotype to established mouse models of protoporphyria (EPP FECHm1Pas/m1Pas, XLPP Alas2Q548X/Y, and IRP2-/-) at baseline. We also challenged animals with iron deficiency and iron overload. Lastly, we investigated the severity of EPP animals in the presence or absence of Alas2-IRE. Results. (a) Phenotype. Alas2ΔLOOP/Y mice have a transitory protoporphyria that resolves nearly completely by 8 weeks of age. The RBC protoporphyric phenotype is similar to XLPP mice, but substantially less severe than the EPP, XLPP, and IRP2 models. (b) Iron status. EPP, XLPP, and Alas2ΔLOOP male animals were challenged with either iron deficiency or iron overload at weaning. In iron-poor conditions, all three models have an increase in erythroid PPIX, with the Alas2ΔLOOPanimals having by far the most dramatic change after 5 weeks (mean MFI PPIX [SD] for Alas2ΔLOOPiron-replete: 12.8[6.0] v. iron poor 752[374]). However, only the Alas2 mutants (XLPP, Alas2ΔLOOP) see a modest but prolonged increase in erythroid PPIX when injected once with iron dextran. (c) Disease modifier. The double mutant Alas2ΔLOOP/Y FECHm1Pas/m1Pas (EPP-ΔLOOP) accumulate more erythroid PPIX than the EPP animals at 8 weeks of age (MFI PPIX mean [SD] for Alas2ΔLOOP 18.8[8.9], EPP 128.6 [19.1], EPP-ΔLOOP 659.6[384.7]). The fraction of fluorocytes (erythroid cells in peripheral blood abnormally containing PPIX) is also increased (%mean [SD] for EPP 57.8[8.9], EPP-ΔLOOP 97.6[2.6]). XLPP animals lacking one allele of IRP2 (Alas2Q548X/Y IRP2wt/-) present a phenotype similar to the EPP-ΔLOOP animals while Alas2Q548X/Y IRP2-/- are not viable. Conclusion. Altogether, our results confirm that iron status strongly modifies the erythroid PPIX accumulation, particularly when Alas2 expression is uncoupled from the IRPs control. We also demonstrated that the IRE-IRP system plays a critical role in mitigating the severity of protoporphyria in the rodents, providing evidence that targeting the Alas2-IRE may have pharmacological benefits.
2024-04-18 | The effects of cholecalciferol and afamelanotide on vitamin D levels in erythropoietic protoporphyria; a multicentre cohort study
Abstract Background Patients with erythropoietic protoporphyria experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that 47–63% of patients with EPP suffer from vitamin D deficiency and a high prevalence of osteoporosis. An effective treatment for EPP has been available since 2016: the α-melanocyte stimulating hormone analogue afamelanotide. So far, studies on vitamin D levels in EPP have only investigated patients who have not been treated with afamelanotide. Objectives To investigate the effects of afamelanotide treatment on vitamin D levels in EPP. Methods A multicentre observational cohort study in adults with EPP from the Erasmus Medical Centre, the Netherlands, and the University Hospital Düsseldorf, Germany, was carried out. Routinely collected vitamin D levels between 2005 and 2021 were used for analysis. Patient exposure to cholecalciferol or afamelanotide was categorized into four treatment groups: untreated, cholecalciferol, afamelanotide and combined treatment. A linear mixed model for longitudinal data was applied to measure the effect of the treatment groups compared with the untreated groups on vitamin D levels. Results A total of 230 patients and 1774 vitamin D measurements were included. The prevalence of vitamin D deficiency and severe deficiency remained high despite afamelanotide treatment (< 50 nmol L–1 in 71.8% of patients and < 30 nmol L–1 in 48.1%, respectively). Afamelanotide treatment alone did not lead to a significant average increase in vitamin D levels [β = 0.5, 95% confidence interval (CI) –3.2 to 4.2]. In contrast, cholecalciferol and combined therapy with afamelanotide led to a significant increase in vitamin D levels [β = 11.6 (95% CI 7.2–15.9) and β = 15.2 (95% CI 12.3–18.1), respectively]. Conclusions Cholecalciferol remains essential for the treatment of vitamin D deficiency in EPP, irrespective of new treatment options like afamelanotide. Afamelanotide treatment did not affect vitamin D levels. We suggest that future guidelines include continuous monitoring of vitamin D and a prescription for cholecalciferol in all patients with EPP, including those treated with afamelanotide.
2021-12-20 | In vitro Assessment of Solar Filters for Erythropoietic Protoporphyria in the Action Spectrum of Protoporphyrin IX
Introduction: Subjects with erythropoietic protoporphyria rely on broad-spectrum sunscreens with high sun protection factor, which is not informative on efficacy in the absorption spectrum of protoporphyrin IX, spanning visible radiation and peaking around 408 nm. Photoactivation of protoporphyrin IX is responsible for painful skin photosensitivity in erythropoietic protoporphyria. The authors assessed the protective efficacy of six sunscreens in vitro in the absorption spectrum of protoporphyrin IX. Method: Transmittance measurements were performed in the 300–850 nm wavelengths on samples of six photoprotective products applied to polymethyl methacrylate plates. Porphyrin protection factor was calculated in the 300–700 nm region to provide a measurement for the efficacy of each product based on the action spectrum of protoporphyrin IX. Results: Product A showed the highest porphyrin protection factor among tested products with a median value of 4.22. Product A is a sunscreen containing organic filters, titanium dioxide and synthetic iron oxides, pigmentary grade active ingredients that absorb visible radiation. Other products showed inefficient protection in the visible, with transmittance between 75 and 95% at 500 nm. The low porphyrin protection factor of inorganic filter product B was attributed to particle micronization, as declared by the manufacturer. Conclusion: Adding porphyrin protection factor to sunscreen labeling could help patients with erythropoietic protoporphyria and other photosensitivity disorders identify products tailored on their specific needs. The development of sunscreens providing protection from visible radiation and excellent cosmetical tolerability could improve the lifestyle of patients with erythropoietic protoporphyria.
gene therapies
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2025-09-17 | Rbm38 deficiency impairs erythroid heme biosynthesis and induces porphyria via reduced ferrochelatase expression.
RNA splicing and processing are critical for erythropoiesis, because dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. Although in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell (RBC) production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- RBCs exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin IX (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, messenger RNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.
2019-03-08 | CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations
Abstract CRISPR-Cas9 is a promising technology for genome editing. Here we use Cas9 nuclease-induced double-strand break DNA (DSB) at the UROS locus to model and correct congenital erythropoietic porphyria. We demonstrate that homology-directed repair is rare compared with NHEJ pathway leading to on-target indels and causing unwanted dysfunctional protein. Moreover, we describe unexpected chromosomal truncations resulting from only one Cas9 nuclease-induced DSB in cell lines and primary cells by a p53-dependent mechanism. Altogether, these side effects may limit the promising perspectives of the CRISPR-Cas9 nuclease system for disease modeling and gene therapy. We show that the single nickase approach could be safer since it prevents on- and off-target indels and chromosomal truncations. These results demonstrate that the single nickase and not the nuclease approach is preferable, not only for modeling disease but also and more importantly for the safe management of future CRISPR-Cas9-mediated gene therapies.
2012-07-01 | Metabolic Correction of Congenital Erythropoietic Porphyria with iPSCs Free of Reprogramming Factors
Congenital erythropoietic porphyria (CEP) is due to a deficiency in the enzymatic activity of uroporphyrinogen III synthase (UROS); such a deficiency leads to porphyrin accumulation and results in skin lesions and hemolytic anemia. CEP is a candidate for retrolentivirus-mediated gene therapy, but recent reports of insertional leukemogenesis underscore the need for safer methods. The discovery of induced pluripotent stem cells (iPSCs) has opened up new horizons in gene therapy because it might overcome the difficulty of obtaining sufficient amounts of autologous hematopoietic stem cells for transplantation and the risk of genotoxicity. In this study, we isolated keratinocytes from a CEP-affected individual and generated iPSCs with two excisable lentiviral vectors. Gene correction of CEP-derived iPSCs was obtained by lentiviral transduction of a therapeutic vector containing UROS cDNA under the control of an erythroid-specific promoter shielded by insulators. One iPSC clone, free of reprogramming genes, was obtained with a single proviral integration of the therapeutic vector in a genomic safe region. Metabolic correction of erythroblasts derived from iPSC clones was demonstrated by the disappearance of fluorocytes. This study reports the feasibility of porphyria gene therapy with the use of iPSCs. Congenital erythropoietic porphyria (CEP) is due to a deficiency in the enzymatic activity of uroporphyrinogen III synthase (UROS); such a deficiency leads to porphyrin accumulation and results in skin lesions and hemolytic anemia. CEP is a candidate for retrolentivirus-mediated gene therapy, but recent reports of insertional leukemogenesis underscore the need for safer methods. The discovery of induced pluripotent stem cells (iPSCs) has opened up new horizons in gene therapy because it might overcome the difficulty of obtaining sufficient amounts of autologous hematopoietic stem cells for transplantation and the risk of genotoxicity. In this study, we isolated keratinocytes from a CEP-affected individual and generated iPSCs with two excisable lentiviral vectors. Gene correction of CEP-derived iPSCs was obtained by lentiviral transduction of a therapeutic vector containing UROS cDNA under the control of an erythroid-specific promoter shielded by insulators. One iPSC clone, free of reprogramming genes, was obtained with a single proviral integration of the therapeutic vector in a genomic safe region. Metabolic correction of erythroblasts derived from iPSC clones was demonstrated by the disappearance of fluorocytes. This study reports the feasibility of porphyria gene therapy with the use of iPSCs.
2011-02-25 | Congenital Erythropoietic Porphyria: Characterization of Murine Models of the Severe Common (C73R/C73R) and Later-Onset Genotypes
Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder due to the deficient activity of uroporphyrinogen III synthase (UROS). Knock-in mouse models were generated for the common, hematologically severe human genotype, C73R/C73R, and milder genotypes (C73R/V99L and V99L/V99L). The specific activities of the UROS enzyme in the livers and erythrocytes of these mice averaged approximately 1.2%, 11% and 19% of normal, respectively. C73R/C73R mice that survived fetal life to weaning age (~12%) had a severe microcytic hypochromic anemia (hemoglobin 7.9 g/dL, mean cellular volume 26.6 fL, mean cellular hemoglobin content 27.4 g/dL, red cell distribution width 37.7%, reticulocytes 19%) and massively accumulated isomer I porphyrins (95, 183 and 44 µmol/L in erythrocytes, spleen and liver, respectively), but a nearly normal lifespan. In adult C73R/C73R mice, spleen and liver weights were 8.2- and 1.5-fold increased, respectively C73R/V99L mice were mildly anemic (hemoglobin was 14.0 g/dL and mean cellular hemoglobin was 13.3), with minimally accumulated porphyrins (0.10, 5.54 and 0.58 µmol/L in erythrocytes, spleen and liver, respectively), whereas adult V99L/V99L mice were normal. Of note, even the mildest genotype, V99L/V99L, exhibited porphyria in utero, which disappeared by 2 months of age. These severe and mild mouse models inform therapeutic interventions and permit further investigation of the porphyrin-induced hematopathology, which leads to photo-induced cutaneous lesions. Of significance for therapeutic intervention, these mouse models suggest that only 11% of wild-type activity might be needed to reverse the pathology in CEP patients.
proteins
2025-03-04 | Congenital erythropoietic porphyria: the overlooked inherited disorder.
Congenital erythropoietic porphyria (CEP) also known as Gunther's disease is a subtype of porphyria. It is an autosomal recessive disorder caused by a mutation in the uroporphyrinogen III gene (URO III) coding for the enzyme UROS synthase, an essential enzyme in the heme synthesis pathway. The condition may present as non-immune hydrops in foetuses, dark-red urine-stained diapers in neonates and skin blistering and mutilation in sun-exposed areas in older children. Enzyme assays and genetic studies are costly and not easily available in low-resource settings; therefore, awareness of the typical phenotype of this rare porphyria is crucial. However, due to the scarcity of reported cases, clinicians remain oblivious to the disease, leading to delays in diagnosis and initiation of treatment, thus contributing to long-term disabilities. We report a case of a male child in early adolescence presenting with classical cutaneous, skeletal and haematological features of CEP.
1970-09-01 | Congenital Erythropoietic Porphyria. II. The Effects of Induced Polycythemia
Abstract Polycythemia and anemia were induced in a patient with congenital erythropoietic porphyria as a possible means of altering erythropoiesis and its attendant porphyrin production. Maintenance of hematocrits at 50 per cent and 60 per cent for periods of 2 weeks decreased both erythropoiesis and porphyrin excretion to about one-half of their initial levels. Conversely with a hematocrit of 25, erythropoiesis and porphyrin production were increased to about twice the basal level. Examination of the marrow showed fluorescence in all late normoblasts and indicated that the patient has only one red cell population. During induced polycythemia, a shift in marrow erythroid population to relatively mature forms, apparently related to delayed enucleation, was accompanied by a retention of the reticulocyte pool and fluorescent cells within the marrow. During anemia, the occurrence of relatively more immature erythroid cells was accompanied by a shift of the reticulocyte pool and fluorescent cells into the circulating blood. During polycythemia, increases were observed in the relative number of nuclear vacuoles peculiar to this disease, in the retention of radioiron in the marrow and in the relative amount of stercobilin excretion. In anemia these parameters decreased towards normal.
1968-03-01 | Determination of a Skin-Related Erythropoietic Substance
SummaryA method is presented for the extraction of a hemin-stimulated, heat stable erythropoietically active fraction (HSP) from the skin of subcutaneously injected animals. The production of HSP is not species specific; similar substances were produced by the enderonic tissues of the cat, guinea pig, rabbit, rat, and mouse. While the production of HSP is coincident with inflammation produced by hemin injection, the production is not inflammation-dependent per se since other inflammatory substances tested do not stimulate production. The HSP compares favorably with erythropoietin Standard B (from human urine) for erythropoietic activity in the fasting “dehydrated” rat. Its activity has also been confirmed in the polycythemic rat. The dose-response curve for HSP administration shows a definite response to as little as 70 μg. The maximal response plateaus at a dose of about 1 mg.
cell therapies
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2025-02-11 | Scavenger endothelial cells alleviate tissue damage by engulfing toxic molecules derived from hemolysis.
Hemolysis induces tissue damage by releasing cellular contents into the plasma. It is widely accepted that hemolysis-derived toxic molecules are cleared by macrophages or metabolized in hepatocytes. In zebrafish, we found that scavenger endothelial cells (SECs), a specialized endothelium with remarkable endocytosis capability, engulf both macromolecular hemoglobin (Hb) and small molecular unconjugated bilirubin (UCB), two primary toxic byproducts of hemolysis. These engulfment processes are mediated by the scavenger receptor Stab2. To demonstrate the protective function of SECs during hemolysis, we employed a zebrafish model of erythropoietic porphyria, characterized by excessive protoporphyrin IX (PPIX) accumulation due to ferrochelatase mutation, leading to light-sensitive hemolysis and larva death. We found that SECs facilitate the clearance of excess PPIX via Stab2, thereby mitigating PPIX-induced larval mortality. In addition, mouse SECs possess a conserved capability of scavenging Hb/UCB/PPIX. In conclusion, our study identifies SECs as a detoxification system during physiological and pathological hemolysis, shedding light on their protective role against hemolysis-induced damage.
2024-01-30 | VERY EARLY DIAGNOSIS AND MANAGEMENT OF CONGENITAL ERYTHROPOIETIC PORPHYRIA AT BIRTH
Congenital erythropoietic porphyria (CEP) is caused by a defect in the heme biosynthesis pathway of the enzyme uroporphyrinogen III synthase (UROS) leading to an accumulation of non-physiological porphyrins. The exposure of accumulated porphyrins to sunlight causes severe photosensitivity, chronic intravascular hemolysis and, eventually, irreversible mutilating deformities. Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusion, hydroxyurea and splenectomy are commonly used in the management of CEP. Currently, the only available curative treatment of CEP is HSCT. We present a child with a very early diagnosis of CEP, who became the youngest successful HSCT for CEP.
2024-01-27 | Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: A case report
Abstract Congenital erythropoietic porphyria (CEP), or Gunther disease, is a rare genetic disease responsible for severe dermatologic, hepatic and/or haematological damages related to the deficient activity of the uroporphyrinogen III synthase. Allogeneic stem cell transplantation (Allo‐SCT) represents the only curative treatment and few allotransplanted cases have been reported in children but not in adults. Here we report for the first time the successful cure of a 46‐year old man with CEP with a 5‐year follow‐up after Allo‐SCT.
2024-01-23 | Severe Perinatal Presentations of Günther's Disease: Series of 20 Cases and Perspectives.
(1) Background: Congenital erythropoietic porphyria (CEP), named Günther's disease, is a rare recessive type of porphyria, resulting from deficient uroporphyrinogen III synthase (UROS), the fourth enzyme of heme biosynthesis. The phenotype ranges from extremely severe perinatal onset, with life-threatening hemolytic anaemia, to mild or moderate cutaneous involvement in late-onset forms. This work reviewed the perinatal CEP cases recorded in France in order to analyse their various presentations and evolution. (2) Methods: Clinical and biological data were retrospectively collected through medical and published records. (3) Results: Twenty CEP cases, who presented with severe manifestations during perinatal period, were classified according to the main course of the disease: antenatal features, acute neonatal distress and postnatal diagnosis. Antenatal symptoms (seven patients) were mainly hydrops fetalis, hepatosplenomegaly, anemia, and malformations. Six of them died prematurely. Five babies showed acute neonatal distress, associated with severe anemia, thrombocytopenia, hepatosplenomegaly, liver dysfunction, and marked photosensitivity leading to diagnosis. The only two neonates who survived underwent hematopoietic stem cell transplantation (HSCT). Common features in post-natal diagnosis (eight patients) included hemolytic anemia, splenomegaly, skin sensitivity, and discoloured teeth and urine. All patients underwent HSCT, with success for six of them, but with fatal complications in two patients. The frequency of the missense variant named C73R is striking in antenatal and neonatal presentations, with 9/12 and 7/8 independent alleles, respectively. (4) Conclusions: The most recent cases in this series are remarkable, as they had a less fatal outcome than expected. Regular transfusions from the intrauterine period and early access to HSCT are the main objectives.
small molecules
2025-12-31 | Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
2025-12-30 | New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide. We identified pharmacotherapies (leaving out, for example, topical applications such as sunscreens or supplements such as iron) which are currently (that is, within the last 5 years) evaluated for EPP from clinical trial registries and investigated whether the trial designs allow a comparison of their treatment effects with each other and with afamelanotide. Therefore, we analysed the clinical trial protocols with emphasis on their trial designs, efficacy outcome measures, inclusion and exclusion criteria, safety aspects and, if available, published results. Our search in the clinical trials registries retrieved 29 trials that included patients with EPP. From these, we identified 16 clinical trials evaluating afamelanotide and three new pharmacotherapies, i.e., dersimelagon, bitopertin and cimetidine. Safety and efficacy of all new pharmacotherapies are currently being investigated against placebo-control groups or against baseline. Because of differences in the outcome measures and included patient populations, the results of the trials cannot be directly compared. Moreover, methodically challenging aspects and ethical issues were identified in some of the trial protocols. Efficacy and safety of currently investigated treatments for EPP are not directly comparable. We wrote this manuscript as a call to action to Principal Investigators, Ethical Review Boards, Regulatory Authorities and the sponsors of trials because we are convinced that trials directly assessing new pharmacotherapies against afamelanotide would be the more informative, and methodological and ethically sounder trial design. Not applicable. The online version contains supplementary material available at 10.1186/s13023-025-04170-9.
2024-11-05 | Uncoupling Alas2 from Iron-Regulatory Proteins Demonstrates the Protective Role of Alas2 Iron-Responsive Element in Protoporphyrias
Introduction. Many genes relevant to iron metabolism include a transcribed cis-regulatory element called iron-responsive element (IRE) that couples their expression to the availability of intracellular iron. Canonical IREs consist of a conserved stem-loop structure in the 5‘ or 3‘ untranslated region (UTR) of these mRNAs. IREs are bound by two iron-regulatory proteins (IRP1 & IRP2) to either limit the translation of the targeted transcript or to stabilize it. Among the 5'UTR IRE- genes, ALAS2, the erythroid-specific aminolevulinate synthase, catalyzes the first step of heme biosynthesis. Loss-of-function and gain-of-function mutations cause X-linked Sideroblastic Anemia (XLSA) and X-linked Protoporphyria (XLPP). A deficiency in the last enzyme of the pathway, ferrochelatase (FECH), causes the most common Erythropoietic Protoporphyria (EPP). A single-family with protoporphyria has been described with a mutation in the mitochondrial unfoldase CLPX. In the mouse, targeted deletion of IRP2 also results in protoporphyria. Several lines of evidence suggest a role for Alas2 in modifying the severity of erythroid porphyrias. In 4 patients with congenital erythropoietic porphyria due to the same UROS genotype, an XLPP mutation was also found in the most severely affected individual. A mutation in the Alas2-IRE has been described as a modifier in the CLPX-family. Furthermore, increased levels of Alas2 mRNA have been reported in EPP patients. Lastly, other reports suggest that iron deficiency may be protective in protoporphyrias. Methods. We generated a mouse line lacking the loop of Alas2-IRE (Alas2ΔLOOP), which should uncouple ALAS2 expression from IRP-dependent regulation. We phenotyped hemizygous male Alas2ΔLOOP/Y mice from 1 to 8 weeks of age. We compared their phenotype to established mouse models of protoporphyria (EPP FECHm1Pas/m1Pas, XLPP Alas2Q548X/Y, and IRP2-/-) at baseline. We also challenged animals with iron deficiency and iron overload. Lastly, we investigated the severity of EPP animals in the presence or absence of Alas2-IRE. Results. (a) Phenotype. Alas2ΔLOOP/Y mice have a transitory protoporphyria that resolves nearly completely by 8 weeks of age. The RBC protoporphyric phenotype is similar to XLPP mice, but substantially less severe than the EPP, XLPP, and IRP2 models. (b) Iron status. EPP, XLPP, and Alas2ΔLOOP male animals were challenged with either iron deficiency or iron overload at weaning. In iron-poor conditions, all three models have an increase in erythroid PPIX, with the Alas2ΔLOOPanimals having by far the most dramatic change after 5 weeks (mean MFI PPIX [SD] for Alas2ΔLOOPiron-replete: 12.8[6.0] v. iron poor 752[374]). However, only the Alas2 mutants (XLPP, Alas2ΔLOOP) see a modest but prolonged increase in erythroid PPIX when injected once with iron dextran. (c) Disease modifier. The double mutant Alas2ΔLOOP/Y FECHm1Pas/m1Pas (EPP-ΔLOOP) accumulate more erythroid PPIX than the EPP animals at 8 weeks of age (MFI PPIX mean [SD] for Alas2ΔLOOP 18.8[8.9], EPP 128.6 [19.1], EPP-ΔLOOP 659.6[384.7]). The fraction of fluorocytes (erythroid cells in peripheral blood abnormally containing PPIX) is also increased (%mean [SD] for EPP 57.8[8.9], EPP-ΔLOOP 97.6[2.6]). XLPP animals lacking one allele of IRP2 (Alas2Q548X/Y IRP2wt/-) present a phenotype similar to the EPP-ΔLOOP animals while Alas2Q548X/Y IRP2-/- are not viable. Conclusion. Altogether, our results confirm that iron status strongly modifies the erythroid PPIX accumulation, particularly when Alas2 expression is uncoupled from the IRPs control. We also demonstrated that the IRE-IRP system plays a critical role in mitigating the severity of protoporphyria in the rodents, providing evidence that targeting the Alas2-IRE may have pharmacological benefits.
2024-04-18 | The effects of cholecalciferol and afamelanotide on vitamin D levels in erythropoietic protoporphyria; a multicentre cohort study
Abstract Background Patients with erythropoietic protoporphyria experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that 47–63% of patients with EPP suffer from vitamin D deficiency and a high prevalence of osteoporosis. An effective treatment for EPP has been available since 2016: the α-melanocyte stimulating hormone analogue afamelanotide. So far, studies on vitamin D levels in EPP have only investigated patients who have not been treated with afamelanotide. Objectives To investigate the effects of afamelanotide treatment on vitamin D levels in EPP. Methods A multicentre observational cohort study in adults with EPP from the Erasmus Medical Centre, the Netherlands, and the University Hospital Düsseldorf, Germany, was carried out. Routinely collected vitamin D levels between 2005 and 2021 were used for analysis. Patient exposure to cholecalciferol or afamelanotide was categorized into four treatment groups: untreated, cholecalciferol, afamelanotide and combined treatment. A linear mixed model for longitudinal data was applied to measure the effect of the treatment groups compared with the untreated groups on vitamin D levels. Results A total of 230 patients and 1774 vitamin D measurements were included. The prevalence of vitamin D deficiency and severe deficiency remained high despite afamelanotide treatment (< 50 nmol L–1 in 71.8% of patients and < 30 nmol L–1 in 48.1%, respectively). Afamelanotide treatment alone did not lead to a significant average increase in vitamin D levels [β = 0.5, 95% confidence interval (CI) –3.2 to 4.2]. In contrast, cholecalciferol and combined therapy with afamelanotide led to a significant increase in vitamin D levels [β = 11.6 (95% CI 7.2–15.9) and β = 15.2 (95% CI 12.3–18.1), respectively]. Conclusions Cholecalciferol remains essential for the treatment of vitamin D deficiency in EPP, irrespective of new treatment options like afamelanotide. Afamelanotide treatment did not affect vitamin D levels. We suggest that future guidelines include continuous monitoring of vitamin D and a prescription for cholecalciferol in all patients with EPP, including those treated with afamelanotide.
2021-12-20 | In vitro Assessment of Solar Filters for Erythropoietic Protoporphyria in the Action Spectrum of Protoporphyrin IX
Introduction: Subjects with erythropoietic protoporphyria rely on broad-spectrum sunscreens with high sun protection factor, which is not informative on efficacy in the absorption spectrum of protoporphyrin IX, spanning visible radiation and peaking around 408 nm. Photoactivation of protoporphyrin IX is responsible for painful skin photosensitivity in erythropoietic protoporphyria. The authors assessed the protective efficacy of six sunscreens in vitro in the absorption spectrum of protoporphyrin IX. Method: Transmittance measurements were performed in the 300–850 nm wavelengths on samples of six photoprotective products applied to polymethyl methacrylate plates. Porphyrin protection factor was calculated in the 300–700 nm region to provide a measurement for the efficacy of each product based on the action spectrum of protoporphyrin IX. Results: Product A showed the highest porphyrin protection factor among tested products with a median value of 4.22. Product A is a sunscreen containing organic filters, titanium dioxide and synthetic iron oxides, pigmentary grade active ingredients that absorb visible radiation. Other products showed inefficient protection in the visible, with transmittance between 75 and 95% at 500 nm. The low porphyrin protection factor of inorganic filter product B was attributed to particle micronization, as declared by the manufacturer. Conclusion: Adding porphyrin protection factor to sunscreen labeling could help patients with erythropoietic protoporphyria and other photosensitivity disorders identify products tailored on their specific needs. The development of sunscreens providing protection from visible radiation and excellent cosmetical tolerability could improve the lifestyle of patients with erythropoietic protoporphyria.
gene therapies
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2025-09-17 | Rbm38 deficiency impairs erythroid heme biosynthesis and induces porphyria via reduced ferrochelatase expression.
RNA splicing and processing are critical for erythropoiesis, because dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. Although in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell (RBC) production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- RBCs exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin IX (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, messenger RNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.
2019-03-08 | CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations
Abstract CRISPR-Cas9 is a promising technology for genome editing. Here we use Cas9 nuclease-induced double-strand break DNA (DSB) at the UROS locus to model and correct congenital erythropoietic porphyria. We demonstrate that homology-directed repair is rare compared with NHEJ pathway leading to on-target indels and causing unwanted dysfunctional protein. Moreover, we describe unexpected chromosomal truncations resulting from only one Cas9 nuclease-induced DSB in cell lines and primary cells by a p53-dependent mechanism. Altogether, these side effects may limit the promising perspectives of the CRISPR-Cas9 nuclease system for disease modeling and gene therapy. We show that the single nickase approach could be safer since it prevents on- and off-target indels and chromosomal truncations. These results demonstrate that the single nickase and not the nuclease approach is preferable, not only for modeling disease but also and more importantly for the safe management of future CRISPR-Cas9-mediated gene therapies.
2012-07-01 | Metabolic Correction of Congenital Erythropoietic Porphyria with iPSCs Free of Reprogramming Factors
Congenital erythropoietic porphyria (CEP) is due to a deficiency in the enzymatic activity of uroporphyrinogen III synthase (UROS); such a deficiency leads to porphyrin accumulation and results in skin lesions and hemolytic anemia. CEP is a candidate for retrolentivirus-mediated gene therapy, but recent reports of insertional leukemogenesis underscore the need for safer methods. The discovery of induced pluripotent stem cells (iPSCs) has opened up new horizons in gene therapy because it might overcome the difficulty of obtaining sufficient amounts of autologous hematopoietic stem cells for transplantation and the risk of genotoxicity. In this study, we isolated keratinocytes from a CEP-affected individual and generated iPSCs with two excisable lentiviral vectors. Gene correction of CEP-derived iPSCs was obtained by lentiviral transduction of a therapeutic vector containing UROS cDNA under the control of an erythroid-specific promoter shielded by insulators. One iPSC clone, free of reprogramming genes, was obtained with a single proviral integration of the therapeutic vector in a genomic safe region. Metabolic correction of erythroblasts derived from iPSC clones was demonstrated by the disappearance of fluorocytes. This study reports the feasibility of porphyria gene therapy with the use of iPSCs. Congenital erythropoietic porphyria (CEP) is due to a deficiency in the enzymatic activity of uroporphyrinogen III synthase (UROS); such a deficiency leads to porphyrin accumulation and results in skin lesions and hemolytic anemia. CEP is a candidate for retrolentivirus-mediated gene therapy, but recent reports of insertional leukemogenesis underscore the need for safer methods. The discovery of induced pluripotent stem cells (iPSCs) has opened up new horizons in gene therapy because it might overcome the difficulty of obtaining sufficient amounts of autologous hematopoietic stem cells for transplantation and the risk of genotoxicity. In this study, we isolated keratinocytes from a CEP-affected individual and generated iPSCs with two excisable lentiviral vectors. Gene correction of CEP-derived iPSCs was obtained by lentiviral transduction of a therapeutic vector containing UROS cDNA under the control of an erythroid-specific promoter shielded by insulators. One iPSC clone, free of reprogramming genes, was obtained with a single proviral integration of the therapeutic vector in a genomic safe region. Metabolic correction of erythroblasts derived from iPSC clones was demonstrated by the disappearance of fluorocytes. This study reports the feasibility of porphyria gene therapy with the use of iPSCs.
2011-02-25 | Congenital Erythropoietic Porphyria: Characterization of Murine Models of the Severe Common (C73R/C73R) and Later-Onset Genotypes
Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder due to the deficient activity of uroporphyrinogen III synthase (UROS). Knock-in mouse models were generated for the common, hematologically severe human genotype, C73R/C73R, and milder genotypes (C73R/V99L and V99L/V99L). The specific activities of the UROS enzyme in the livers and erythrocytes of these mice averaged approximately 1.2%, 11% and 19% of normal, respectively. C73R/C73R mice that survived fetal life to weaning age (~12%) had a severe microcytic hypochromic anemia (hemoglobin 7.9 g/dL, mean cellular volume 26.6 fL, mean cellular hemoglobin content 27.4 g/dL, red cell distribution width 37.7%, reticulocytes 19%) and massively accumulated isomer I porphyrins (95, 183 and 44 µmol/L in erythrocytes, spleen and liver, respectively), but a nearly normal lifespan. In adult C73R/C73R mice, spleen and liver weights were 8.2- and 1.5-fold increased, respectively C73R/V99L mice were mildly anemic (hemoglobin was 14.0 g/dL and mean cellular hemoglobin was 13.3), with minimally accumulated porphyrins (0.10, 5.54 and 0.58 µmol/L in erythrocytes, spleen and liver, respectively), whereas adult V99L/V99L mice were normal. Of note, even the mildest genotype, V99L/V99L, exhibited porphyria in utero, which disappeared by 2 months of age. These severe and mild mouse models inform therapeutic interventions and permit further investigation of the porphyrin-induced hematopathology, which leads to photo-induced cutaneous lesions. Of significance for therapeutic intervention, these mouse models suggest that only 11% of wild-type activity might be needed to reverse the pathology in CEP patients.
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Drug Discovery Landscape
3 orphan drug designations for Congenital erythropoietic porphyria.
3 orphan drug designations for Congenital erythropoietic porphyria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ciclopirox | small molecules | FDA | 2018-04-17 | — | Atlas Molecular Pharma S.L. |
Ciclopirox | small molecules | EMA | 2018-01-17 | — | Atlas Molecular Pharma S.L. |
[Nle4, D-Phe7]-alpha-melanocyte stimulating hormone | peptides | EMA | 2008-05-08 | — | Clinuvel Europe Limited |
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