RARE DISEASE
Erythropoietic porphyria
Erythropoietic porphyria
Erythropoietic porphyria
Synonyms: EPP
Synonyms: EPP
Synonyms: EPP
Drug discovery
2
drugs
With orphan designations
Overview
Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder caused by ferrochelatase (FECH) deficiency or ALAS2 mutations (X-linked), leading to protoporphyrin IX accumulation. Patients experience severe phototoxicity with burning pain, erythema, and edema within minutes of sunlight/visible light exposure. Complications include hepatobiliary disease (5-10% develop liver cirrhosis/failure) and protoporphyrin gallstones. Diagnosis requires elevated free erythrocyte protoporphyrin (>80% in EPP; zinc-protoporphyrin predominant in XLP) and genetic confirmation [1][6][9].
Population
Therapies
Photoprotection: Sun avoidance, UV-blocking window films, physical barriers (clothing) [6][17]
Pharmacologic: Afamelanotide (melanocortin-1 agonist implant, improves light tolerance) [9][13], beta-carotene (antioxidant) [6][17]
Monitoring/Advanced Care: Biannual liver function tests, hepatology referral for cholestasis; liver transplant ± bone marrow transplant for end-stage disease [3][7][9]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
255 drug discovery papers about Erythropoietic porphyria, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
255 drug discovery papers about Erythropoietic porphyria, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-26 | New and currently investigated pharmacotherapies for the erythropoietic protoporphyrias: spotlight on dersimelagon and bitopertin.
The erythropoietic protoporphyrias (EPP) are ultra-rare inborn errors of the heme biosynthesis characterized by painful and debilitating phototoxic reactions in the blood vessels upon exposure to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents pain and prolongs the time patients can spend in sunlight. However, afamelanotide does not address the underlying disease mechanism and is currently only approved for use in adult patients, leaving children and adolescents without a treatment option. The two investigational pharmacotherapies, dersimelagon and bitopertin, could offer benefits such as treatment options for children and prevention of some of the associated disease complications. This narrative review (using Pubmed and trial databases) aims to provide an overview of the status of development of dersimelagon and bitopertin, with a focus on the prevention of phototoxicity. The currently available trial data on dersimelagon and bitopertin suggests treatment effects in EPP as compared to placebo control groups. However, safety and efficacy of dersimelagon and bitopertin need to be further characterized. Moreover, to ensure benefit for patients and access to therapy after regulatory approval, it also would be important to generate data on the relative safety and efficacy as compared to afamelanotide.
2025-12-30 | New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
BACKGROUND: 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. METHODS: 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. 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. CONCLUSION: 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. CLINICAL TRIAL NUMBER: Not applicable.
2025-12-14 | Bitopertin shows efficacy in patients with erythropoietic protoporphyria: Results from the randomized, double-blind, placebo-controlled AURORA trial.
Erythropoietic protoporphyria is a rare genetic disorder of heme biosynthesis characterized by protoporphyrin-IX accumulation, painful phototoxic reactions, and hepatobiliary disease, for which no disease-modifying therapies are approved. To evaluate the efficacy and safety of bitopertin, an inhibitor of glycine transporter 1, in adults with erythropoietic protoporphyria. In this randomized, double-blind, phase 2 study, patients received once-daily oral bitopertin 20 mg, bitopertin 60 mg, or placebo for 17 weeks. The primary endpoint was percentage change from baseline in whole-blood metal-free protoporphyrin-IX levels at day 121. Patients received bitopertin 20 mg (n = 26), 60 mg (n = 25), or placebo (n = 24). At day 121, the percentage change from baseline in whole-blood metal-free protoporphyrin-IX versus placebo was -29.6% (P = .004) with bitopertin 20 mg and -49.8% (P < .001) with bitopertin 60 mg. Bitopertin was associated with a reduced incidence of phototoxic reactions. Bitopertin was well tolerated with no notable safety concerns identified. Small sample size, short follow-up period, and no formal adjustments for between-group multiple-pairwise comparisons. Bitopertin significantly reduced protoporphyrin-IX levels, showed improved measures of sunlight tolerance, and had a favorable safety profile in patients with erythropoietic protoporphyria.
2025-01-18 | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic Protoporphyria.
Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase, which inserts iron into protoporphyrin-IX (PP-IX) to generate heme. EPP is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. Despite available drugs that address photosensitivity, treatment of EPP-related liver disease remains an unmet need. We administered delta-aminolevulinic acid (ALA) and deferoxamine (DFO), which results in PP-IX overproduction and accumulation. High-throughput compound screening of ALA + DFO-treated zebrafish identified chlorcyclizine (first generation H1-antihistamine receptor blocker) as a drug that reduces zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes (PMHs), transgenic Fechm1Pas EPP mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction. Chlorcyclizine-treated zebrafish larvae, DDC-fed, and transgenic EPP mice manifested reduced hepatic PP-IX levels compared with controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, whereas H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow; improved liver injury; decreased porphyrin-triggered protein aggregation and oxidation; and increased clearance of stool PP-IX. In PMHs, chlorcyclizine induced nuclear translocation of constitutive androstane and farnesoid X receptors, and transactivated bile acid transporter expression. Knockdown of the transporters BSEP and MRP4 led to increased detection of sequestosome-1 (p62 protein) high-molecular-weight species. Chlorcyclizine also reduced hepatic mast cell number and histamine level in EPP mice. Histamine plays an important role in PP-IX accumulation in zebrafish and 2 experimental EPP models. Chlorcyclizine and/or other antihistamines provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation.
2024-12-05 | Inhibition of ABCG2 prevents phototoxicity in a mouse model of erythropoietic protoporphyria.
Erythropoietic protoporphyria (EPP) is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Currently, options for the management of EPP-associated phototoxicity are limited and no oral medication is available. Here, we investigated a novel therapy against EPP-associated phototoxicity by targeting the ATP-binding cassette subfamily G member 2 (ABCG2), the efflux transporter of protoporphyrin IX. Oral ABCG2 inhibitors were developed, and they successfully prevented EPP-associated phototoxicity in a genetically engineered EPP mouse model. Mechanistically, ABCG2 inhibitors suppress protoporphyrin IX release from erythroid cells and reduce the systemic exposure to protoporphyrin IX in EPP. In summary, our work establishes a novel strategy for EPP therapy by targeting ABCG2 and provides oral ABCG2 inhibitors that can effectively prevent protoporphyrin IX-mediated phototoxicity in mice.
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.
2025-02-19 | Paternal Split-Liver Transplantation Followed by Haploidentical Hematopoietic Cell Transplantation in an Adult Patient With Protoporphyria-Induced Liver Failure.
Erythropoietic Protoporphyria (EPP) caused skin light sensitivity and liver cirrhosis in a 35-year-old patient who subsequently developed liver-failure. In absence of a human leukocyte antigens (HLA)-matched-unrelated donor, the father consented in donating for split liver transplantation (SLT) and allogeneic hematopoietic cell transplantation (HCT). After bridging therapy and successful SLT a first paternal HCT resulted in graft failure. For a second haploidentical HCT a different regimen was applied leading to engraftment while protoporphyrin (PP) blood-levels decreased to normal and skin light sensitivity skin disappeared, leading to complete remission in an immunosuppressive-free patient. Haploidentical transplantation is a feasible treatment approach in EPP-patients. The authors have confirmed clinical trial registration is not needed for this submission.
2024-07-01 | Successful treatment of severe hepatic impairment in erythropoietic protoporphyria: A case report and review of literature.
Erythropoietic protoporphyria (EPP) is a rare genetic disorder stemming from ferrochelatase gene mutations, which leads to abnormal accumulation of protoporphyrin IX primarily in erythrocytes, skin, bone marrow and liver. Although porphyria-related severe liver damage is rare, its consequences can be severe with limited treatment options. This case study highlights a successful intervention for a 35-year-old male with EPP-related liver impairment, employing a combination of red blood cell (RBC) exchange and therapeutic plasma exchange (TPE). The patient experienced significant symptom relief and a decrease in bilirubin levels following multiple PE sessions and an RBC exchange. The findings suggest that this combined approach holds promise for managing severe hepatic impairment in EPP.
2022-03-16 | Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients.
Cutaneous, hematopoietic, and hepatic manifestations of congenital erythropoietic porphyria (CEP) and erythropoietic protoporphyria (EPP) can be debilitating. We present our institution's experience with five patients with porphyria who underwent hematopoietic stem cell transplant (HSCT). Four patients with CEP, including three under age 2, received myeloablation. One patient with EPP, with prior liver transplant, received reduced intensity conditioning (RIC). Four patients are alive without porphyria symptomology and with full donor chimerism. HSCT corrects the defective heme pathway and should be considered early in patients with severe erythropoietic porphyrias to minimize end-organ damage. RIC regimens can minimize toxicity in patients with comorbidities.
2022-03-14 | Cardiopulmonary bypass in a child with erythropoietic protoporphyria.
Children with erythropoietic porphyria are generally under the care of paediatric dermatologists. When these children undergo major surgery, they are at risk of unusual complications due to their photosensitivity. Dermatologists may be consulted prior to surgery for advice. We describe a case of a child with erythropoietic porphyria undergoing open heart surgery, utilising an exchange transfusion alongside other strategies to minimise the risk of photosensitivity-induced haemolysis.
proteins
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.
2025-09-17 | 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.
2025-08-27 | Erythropoietic protoporphyria in childhood: clinical clues, missed diagnoses and emerging therapy.
Erythropoietic protoporphyria (EPP) is a rare photodermatosis presenting in early childhood with severe pain upon exposure to visible light, including sunlight and artificial sources, often without visible skin changes in the early phase. However, skin changes such as erythema, oedema or crusting may develop after prolonged exposure. This mini-review highlights key clinical features and proposes a structured diagnostic approach, illustrated by a representative paediatric case. Emerging therapies, including off-label afamelanotide and experimental visible light protection, are discussed alongside practical management in primary care. The review also addresses the psychosocial impact and systemic challenges in European care structures. The aim is to raise awareness among paediatricians and general practitioners, promote earlier diagnosis and support equitable care for affected children. What is Known: • EPP is the most common porphyria in childhood. It typically manifests with painful photosensitivity and no visible skin changes. Despite characteristic features, diagnosis is often delayed due to low awareness in paediatric care. What is New: • This mini-review proposes a practical diagnostic algorithm for paediatric primary care and highlights key clinical clues to sensitise general paediatricians to EPP. It also reviews emerging treatment options such as afamelanotide, already approved for adults, with promising adolescent data. These advances must now be widely communicated and translated into equitable access for children across Europe.
2025-03-14 | German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP).
Afamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation. Evaluate the short- and long-term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany. The PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment-emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP-QoL tool and through treatment continuity. The short- and long-term safety and benefit-risk profile of afamelanotide under real-world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population. Afamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.
2024-07-16 | Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management.
The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.
oligonucleotides
2024-08-29 | Exploring current and emerging therapies for porphyrias.
Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.
2020-01-28 | Mild iron deficiency does not ameliorate the phenotype of a murine erythropoietic protoporphyria model
Abstract Reduced ferrochelatase activity in erythropoietic protoporphyria (EPP) causes the accumulation of protoporphyrin IX (PPIX) leading to acute cutaneous photosensitivity and liver injury. Many EPP patients also have a mild hypochromic, microcytic anemia and iron deficiency. Iron deficiency can lead to decreased PPIX accumulation in another erythropoietic porphyria, congenital erythropoietic porphyria (CEP). Expression of the iron regulatory peptide hepcidin is negatively regulated by the serine protease TMPRSS6 . Hepcidin induction by siRNA‐mediated inhibition of TMPRSS6 expression reduces iron availability and induces iron deficiency. To interrogate the therapeutic potential of iron deficiency to modify EPP, we treated an ethylnitrosourea‐induced mouse model of EPP, Fech m1Pas , with a GalNAc ‐ conjugated Tmprss6 siRNA and PPIX levels, anemia and iron parameters were monitored. The GalNAc‐RNAi therapeutic reduces Tmprss6 expression and induces mild iron deficiency in Fech m1Pas animals. However, decreases in erythrocyte PPIX levels and liver PPIX accumulation were not seen. These results indicate short‐term induction of iron deficiency, at least in a murine model of EPP, does not lead to decreased PPIX production.
2018-10-16 | Long non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development
In addition to serving as a prosthetic group for enzymes and a hemoglobin structural component, heme is a crucial homeostatic regulator of erythroid cell development and function. While lncRNAs modulate diverse physiological and pathological cellular processes, their involvement in heme-dependent mechanisms is largely unexplored. In this study, we elucidated a lncRNA (UCA1)-mediated mechanism that regulates heme metabolism in human erythroid cells. We discovered that UCA1 expression is dynamically regulated during human erythroid maturation, with a maximal expression in proerythroblasts. UCA1 depletion predominantly impairs heme biosynthesis and arrests erythroid differentiation at the proerythroblast stage. Mechanistic analysis revealed that UCA1 physically interacts with the RNA-binding protein PTBP1, and UCA1 functions as an RNA scaffold to recruit PTBP1 to ALAS2 mRNA, which stabilizes ALAS2 mRNA. These results define a lncRNA-mediated posttranscriptional mechanism that provides a new dimension into how the fundamental heme biosynthetic process is regulated as a determinant of erythrocyte development.
2017-12-05 | Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice.
Erythropoietic protoporphyria (EPP) is caused by deficiency of ferrochelatase (FECH), which incorporates iron into protoporphyrin IX (PPIX) to form heme. Excitation of accumulated PPIX by light generates oxygen radicals that evoke excessive pain and, after longer light exposure, cause ulcerations in exposed skin areas of individuals with EPP. Moreover, ∼5% of the patients develop a liver dysfunction as a result of PPIX accumulation. Most patients (∼97%) have a severe FECH mutation (Mut) in trans to an intronic polymorphism (c.315-48C), which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3' splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas) show a very strong EPP phenotype that includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after a short period of light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing.
2017-01-21 | Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments
Purpose of review Many studies over the past decade have together identified new genes including modifier genes and new regulation and pathophysiological mechanisms in inherited inborn diseases of the heme biosynthetic pathway. A new porphyria has been characterized: X-linked protoporphyria and the perspective to have innovative treatment at very short-term became a reality. We will summarize how recent data on both ALAS1 and ALAS2 have informed our understanding of disease pathogenesis with an emphasis on how this information may contribute to new therapeutic strategies. Recent findings The development of clinical and biological porphyria networks improved the long-term follow up of cohorts. The ageing of patients have allowed for the identification of novel recurrently mutated genes, and highlighted long-term complications in acute hepatic porphyrias. The treatment of hepatic porphyrias by an RNAi-targeting hepatic ALAS1 is actually tested and may lead to improve the management of acute attacks. In erythropoietic porphyrias, the key role of ALAS2 as a gate keeper of the heme and subsequently hemoglobin synthesis has been demonstrated. Its implication as a modifier gene in over erythroid disorders has also been documented. Summary The knowledge of both the genetic abnormalities and the regulation of heme biosynthesis has increased over the last 5 years and open new avenues in the management of erythropoietic and acute hepatic porphyrias.
other
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.
small molecules
2026-03-26 | New and currently investigated pharmacotherapies for the erythropoietic protoporphyrias: spotlight on dersimelagon and bitopertin.
The erythropoietic protoporphyrias (EPP) are ultra-rare inborn errors of the heme biosynthesis characterized by painful and debilitating phototoxic reactions in the blood vessels upon exposure to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents pain and prolongs the time patients can spend in sunlight. However, afamelanotide does not address the underlying disease mechanism and is currently only approved for use in adult patients, leaving children and adolescents without a treatment option. The two investigational pharmacotherapies, dersimelagon and bitopertin, could offer benefits such as treatment options for children and prevention of some of the associated disease complications. This narrative review (using Pubmed and trial databases) aims to provide an overview of the status of development of dersimelagon and bitopertin, with a focus on the prevention of phototoxicity. The currently available trial data on dersimelagon and bitopertin suggests treatment effects in EPP as compared to placebo control groups. However, safety and efficacy of dersimelagon and bitopertin need to be further characterized. Moreover, to ensure benefit for patients and access to therapy after regulatory approval, it also would be important to generate data on the relative safety and efficacy as compared to afamelanotide.
2025-12-30 | New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
BACKGROUND: 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. METHODS: 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. 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. CONCLUSION: 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. CLINICAL TRIAL NUMBER: Not applicable.
2025-12-14 | Bitopertin shows efficacy in patients with erythropoietic protoporphyria: Results from the randomized, double-blind, placebo-controlled AURORA trial.
Erythropoietic protoporphyria is a rare genetic disorder of heme biosynthesis characterized by protoporphyrin-IX accumulation, painful phototoxic reactions, and hepatobiliary disease, for which no disease-modifying therapies are approved. To evaluate the efficacy and safety of bitopertin, an inhibitor of glycine transporter 1, in adults with erythropoietic protoporphyria. In this randomized, double-blind, phase 2 study, patients received once-daily oral bitopertin 20 mg, bitopertin 60 mg, or placebo for 17 weeks. The primary endpoint was percentage change from baseline in whole-blood metal-free protoporphyrin-IX levels at day 121. Patients received bitopertin 20 mg (n = 26), 60 mg (n = 25), or placebo (n = 24). At day 121, the percentage change from baseline in whole-blood metal-free protoporphyrin-IX versus placebo was -29.6% (P = .004) with bitopertin 20 mg and -49.8% (P < .001) with bitopertin 60 mg. Bitopertin was associated with a reduced incidence of phototoxic reactions. Bitopertin was well tolerated with no notable safety concerns identified. Small sample size, short follow-up period, and no formal adjustments for between-group multiple-pairwise comparisons. Bitopertin significantly reduced protoporphyrin-IX levels, showed improved measures of sunlight tolerance, and had a favorable safety profile in patients with erythropoietic protoporphyria.
2025-01-18 | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic Protoporphyria.
Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase, which inserts iron into protoporphyrin-IX (PP-IX) to generate heme. EPP is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. Despite available drugs that address photosensitivity, treatment of EPP-related liver disease remains an unmet need. We administered delta-aminolevulinic acid (ALA) and deferoxamine (DFO), which results in PP-IX overproduction and accumulation. High-throughput compound screening of ALA + DFO-treated zebrafish identified chlorcyclizine (first generation H1-antihistamine receptor blocker) as a drug that reduces zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes (PMHs), transgenic Fechm1Pas EPP mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction. Chlorcyclizine-treated zebrafish larvae, DDC-fed, and transgenic EPP mice manifested reduced hepatic PP-IX levels compared with controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, whereas H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow; improved liver injury; decreased porphyrin-triggered protein aggregation and oxidation; and increased clearance of stool PP-IX. In PMHs, chlorcyclizine induced nuclear translocation of constitutive androstane and farnesoid X receptors, and transactivated bile acid transporter expression. Knockdown of the transporters BSEP and MRP4 led to increased detection of sequestosome-1 (p62 protein) high-molecular-weight species. Chlorcyclizine also reduced hepatic mast cell number and histamine level in EPP mice. Histamine plays an important role in PP-IX accumulation in zebrafish and 2 experimental EPP models. Chlorcyclizine and/or other antihistamines provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation.
2024-12-05 | Inhibition of ABCG2 prevents phototoxicity in a mouse model of erythropoietic protoporphyria.
Erythropoietic protoporphyria (EPP) is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Currently, options for the management of EPP-associated phototoxicity are limited and no oral medication is available. Here, we investigated a novel therapy against EPP-associated phototoxicity by targeting the ATP-binding cassette subfamily G member 2 (ABCG2), the efflux transporter of protoporphyrin IX. Oral ABCG2 inhibitors were developed, and they successfully prevented EPP-associated phototoxicity in a genetically engineered EPP mouse model. Mechanistically, ABCG2 inhibitors suppress protoporphyrin IX release from erythroid cells and reduce the systemic exposure to protoporphyrin IX in EPP. In summary, our work establishes a novel strategy for EPP therapy by targeting ABCG2 and provides oral ABCG2 inhibitors that can effectively prevent protoporphyrin IX-mediated phototoxicity in mice.
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.
2025-02-19 | Paternal Split-Liver Transplantation Followed by Haploidentical Hematopoietic Cell Transplantation in an Adult Patient With Protoporphyria-Induced Liver Failure.
Erythropoietic Protoporphyria (EPP) caused skin light sensitivity and liver cirrhosis in a 35-year-old patient who subsequently developed liver-failure. In absence of a human leukocyte antigens (HLA)-matched-unrelated donor, the father consented in donating for split liver transplantation (SLT) and allogeneic hematopoietic cell transplantation (HCT). After bridging therapy and successful SLT a first paternal HCT resulted in graft failure. For a second haploidentical HCT a different regimen was applied leading to engraftment while protoporphyrin (PP) blood-levels decreased to normal and skin light sensitivity skin disappeared, leading to complete remission in an immunosuppressive-free patient. Haploidentical transplantation is a feasible treatment approach in EPP-patients. The authors have confirmed clinical trial registration is not needed for this submission.
2024-07-01 | Successful treatment of severe hepatic impairment in erythropoietic protoporphyria: A case report and review of literature.
Erythropoietic protoporphyria (EPP) is a rare genetic disorder stemming from ferrochelatase gene mutations, which leads to abnormal accumulation of protoporphyrin IX primarily in erythrocytes, skin, bone marrow and liver. Although porphyria-related severe liver damage is rare, its consequences can be severe with limited treatment options. This case study highlights a successful intervention for a 35-year-old male with EPP-related liver impairment, employing a combination of red blood cell (RBC) exchange and therapeutic plasma exchange (TPE). The patient experienced significant symptom relief and a decrease in bilirubin levels following multiple PE sessions and an RBC exchange. The findings suggest that this combined approach holds promise for managing severe hepatic impairment in EPP.
2022-03-16 | Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients.
Cutaneous, hematopoietic, and hepatic manifestations of congenital erythropoietic porphyria (CEP) and erythropoietic protoporphyria (EPP) can be debilitating. We present our institution's experience with five patients with porphyria who underwent hematopoietic stem cell transplant (HSCT). Four patients with CEP, including three under age 2, received myeloablation. One patient with EPP, with prior liver transplant, received reduced intensity conditioning (RIC). Four patients are alive without porphyria symptomology and with full donor chimerism. HSCT corrects the defective heme pathway and should be considered early in patients with severe erythropoietic porphyrias to minimize end-organ damage. RIC regimens can minimize toxicity in patients with comorbidities.
2022-03-14 | Cardiopulmonary bypass in a child with erythropoietic protoporphyria.
Children with erythropoietic porphyria are generally under the care of paediatric dermatologists. When these children undergo major surgery, they are at risk of unusual complications due to their photosensitivity. Dermatologists may be consulted prior to surgery for advice. We describe a case of a child with erythropoietic porphyria undergoing open heart surgery, utilising an exchange transfusion alongside other strategies to minimise the risk of photosensitivity-induced haemolysis.
proteins
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.
2025-09-17 | 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.
2025-08-27 | Erythropoietic protoporphyria in childhood: clinical clues, missed diagnoses and emerging therapy.
Erythropoietic protoporphyria (EPP) is a rare photodermatosis presenting in early childhood with severe pain upon exposure to visible light, including sunlight and artificial sources, often without visible skin changes in the early phase. However, skin changes such as erythema, oedema or crusting may develop after prolonged exposure. This mini-review highlights key clinical features and proposes a structured diagnostic approach, illustrated by a representative paediatric case. Emerging therapies, including off-label afamelanotide and experimental visible light protection, are discussed alongside practical management in primary care. The review also addresses the psychosocial impact and systemic challenges in European care structures. The aim is to raise awareness among paediatricians and general practitioners, promote earlier diagnosis and support equitable care for affected children. What is Known: • EPP is the most common porphyria in childhood. It typically manifests with painful photosensitivity and no visible skin changes. Despite characteristic features, diagnosis is often delayed due to low awareness in paediatric care. What is New: • This mini-review proposes a practical diagnostic algorithm for paediatric primary care and highlights key clinical clues to sensitise general paediatricians to EPP. It also reviews emerging treatment options such as afamelanotide, already approved for adults, with promising adolescent data. These advances must now be widely communicated and translated into equitable access for children across Europe.
2025-03-14 | German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP).
Afamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation. Evaluate the short- and long-term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany. The PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment-emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP-QoL tool and through treatment continuity. The short- and long-term safety and benefit-risk profile of afamelanotide under real-world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population. Afamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.
2024-07-16 | Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management.
The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.
oligonucleotides
2024-08-29 | Exploring current and emerging therapies for porphyrias.
Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.
2020-01-28 | Mild iron deficiency does not ameliorate the phenotype of a murine erythropoietic protoporphyria model
Abstract Reduced ferrochelatase activity in erythropoietic protoporphyria (EPP) causes the accumulation of protoporphyrin IX (PPIX) leading to acute cutaneous photosensitivity and liver injury. Many EPP patients also have a mild hypochromic, microcytic anemia and iron deficiency. Iron deficiency can lead to decreased PPIX accumulation in another erythropoietic porphyria, congenital erythropoietic porphyria (CEP). Expression of the iron regulatory peptide hepcidin is negatively regulated by the serine protease TMPRSS6 . Hepcidin induction by siRNA‐mediated inhibition of TMPRSS6 expression reduces iron availability and induces iron deficiency. To interrogate the therapeutic potential of iron deficiency to modify EPP, we treated an ethylnitrosourea‐induced mouse model of EPP, Fech m1Pas , with a GalNAc ‐ conjugated Tmprss6 siRNA and PPIX levels, anemia and iron parameters were monitored. The GalNAc‐RNAi therapeutic reduces Tmprss6 expression and induces mild iron deficiency in Fech m1Pas animals. However, decreases in erythrocyte PPIX levels and liver PPIX accumulation were not seen. These results indicate short‐term induction of iron deficiency, at least in a murine model of EPP, does not lead to decreased PPIX production.
2018-10-16 | Long non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development
In addition to serving as a prosthetic group for enzymes and a hemoglobin structural component, heme is a crucial homeostatic regulator of erythroid cell development and function. While lncRNAs modulate diverse physiological and pathological cellular processes, their involvement in heme-dependent mechanisms is largely unexplored. In this study, we elucidated a lncRNA (UCA1)-mediated mechanism that regulates heme metabolism in human erythroid cells. We discovered that UCA1 expression is dynamically regulated during human erythroid maturation, with a maximal expression in proerythroblasts. UCA1 depletion predominantly impairs heme biosynthesis and arrests erythroid differentiation at the proerythroblast stage. Mechanistic analysis revealed that UCA1 physically interacts with the RNA-binding protein PTBP1, and UCA1 functions as an RNA scaffold to recruit PTBP1 to ALAS2 mRNA, which stabilizes ALAS2 mRNA. These results define a lncRNA-mediated posttranscriptional mechanism that provides a new dimension into how the fundamental heme biosynthetic process is regulated as a determinant of erythrocyte development.
2017-12-05 | Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice.
Erythropoietic protoporphyria (EPP) is caused by deficiency of ferrochelatase (FECH), which incorporates iron into protoporphyrin IX (PPIX) to form heme. Excitation of accumulated PPIX by light generates oxygen radicals that evoke excessive pain and, after longer light exposure, cause ulcerations in exposed skin areas of individuals with EPP. Moreover, ∼5% of the patients develop a liver dysfunction as a result of PPIX accumulation. Most patients (∼97%) have a severe FECH mutation (Mut) in trans to an intronic polymorphism (c.315-48C), which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3' splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas) show a very strong EPP phenotype that includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after a short period of light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing.
2017-01-21 | Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments
Purpose of review Many studies over the past decade have together identified new genes including modifier genes and new regulation and pathophysiological mechanisms in inherited inborn diseases of the heme biosynthetic pathway. A new porphyria has been characterized: X-linked protoporphyria and the perspective to have innovative treatment at very short-term became a reality. We will summarize how recent data on both ALAS1 and ALAS2 have informed our understanding of disease pathogenesis with an emphasis on how this information may contribute to new therapeutic strategies. Recent findings The development of clinical and biological porphyria networks improved the long-term follow up of cohorts. The ageing of patients have allowed for the identification of novel recurrently mutated genes, and highlighted long-term complications in acute hepatic porphyrias. The treatment of hepatic porphyrias by an RNAi-targeting hepatic ALAS1 is actually tested and may lead to improve the management of acute attacks. In erythropoietic porphyrias, the key role of ALAS2 as a gate keeper of the heme and subsequently hemoglobin synthesis has been demonstrated. Its implication as a modifier gene in over erythroid disorders has also been documented. Summary The knowledge of both the genetic abnormalities and the regulation of heme biosynthesis has increased over the last 5 years and open new avenues in the management of erythropoietic and acute hepatic porphyrias.
other
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Erythropoietic porphyria, including 1 approved therapy.
2 orphan drug designations for Erythropoietic porphyria, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
bitopertin | small molecules | FDA | 2022-12-22 | — | Disc Medicine |
Afamelanotide [Scenesse] | peptides | EMA | 2008-05-08 | 2014-12-29 | Clinuvel Europe Limited |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.