RARE DISEASE
Autosomal erythropoietic protoporphyria
Autosomal erythropoietic protoporphyria
Autosomal erythropoietic protoporphyria
Synonyms: EPP
Synonyms: EPP
Synonyms: EPP
Drug discovery
2
drugs
With orphan designations
Overview
Autosomal erythropoietic protoporphyria (EPP) is a rare genetic disorder caused by ferrochelatase (FECH) deficiency, leading to protoporphyrin accumulation in blood and tissues. It manifests as acute, painful photosensitivity typically beginning in early childhood after sunlight exposure (400–410 nm wavelengths) [1][3][5]. Chronic complications include hepatobiliary disease (e.g., protoporphyric liver failure) and gallstones [1][4][8]. Diagnosis involves elevated erythrocyte protoporphyrin levels, plasma fluorescence testing, and FECH genetic analysis [1][4][5]. Therapeutic goals focus on photoprotection and preventing liver damage [1][3][4].
Therapies
Photoprotection: Opaque sunscreens, protective clothing, and window filters to block Soret band light [1][3][8]
Pharmacologic: Afamelanotide (melanocortin analog) improves light tolerance; dersimelagon and bitopertin under clinical evaluation [1][4][6]
Liver management: Annual hepatic monitoring, cholestyramine for protoporphyrin excretion, and liver/bone marrow transplantation for advanced disease [1][3][8]
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
333 drug discovery papers about Autosomal erythropoietic protoporphyria, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
333 drug discovery papers about Autosomal erythropoietic protoporphyria, with 4 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
2026-09-06 | Review of the European Society for Photodynamic Therapy (Euro-PDT) Annual Congress 2025.
This article reviews novel data presented at the 2025 Annual Congress of the European Society for Photodynamic Therapy (Euro-PDT). Photodynamic therapy (PDT) has been investigated for the treatment of a broad spectrum of neoplastic, infectious and inflammatory dermatoses. PDT remains an effective treatment for actinic keratoses/field cancerization with increased interest in delivery of treatment indoors using artificial daylight sources as well as in home-administered daylight PDT. Sustained clearance has remained an important marker of the success of PDT for superficial and thin nodular basal cell carcinomas and updated data is presented. New studies confirm the potential for wider use of PDT for bacterial, fungal, and viral infections, including refractory cutaneous and mucosal warts, with encouraging results also in the treatment of necrobiosis lipoidica and erythropoietic protoporphyria.
2026-09-04 | Seasonal variations in erythropoietic protoporphyria patients' responses about sun behaviour, symptoms, and treatment effect.
Patients with erythropoietic protoporphyria (EPP) have highly variable, increased levels of erythrocyte protoporphyrin IX (PpIX). Upon exposure to visible light, the PpIX is released from the erythrocytes to the skin, producing phototoxic reactions. Severe photosensitivity heavily impacts the patients' daily behavior regarding sun exposure and outdoor life. As patients with EPP in Northern European countries may be free of symptoms during winter, their individual evaluation of sun behavior in summer, the severity of summer symptoms, and effect of oral treatment with Cimetidine and/or zinc sulphate may vary greatly depending on season when answering our EPP DLQI questionnaire. Nineteen patients with EPP answered questions in both mid-summer and the following mid-winter, respectively. The patients' sun behavior was identical when asked both summer and winter. Symptoms were reported as worse in winter than in summer. Treatment effect on symptoms was reported as better in summer than recalled when patients were asked the same question in winter. Erythrocyte PpIX decreased by 14 µmol/L during treatment. These observations may help the clinician decide when to schedule follow-up consultations for patients with EPP.
2026-08-20 | Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
2026-07-30 | An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
2026-05-11 | Heme arginate improves acute liver failure secondary to erythropoietic protoporphyria: a case report.
Erythropoietic protoporphyria (EPP) is a rare inherited disorder with limited therapeutic options. For EPP patients with advanced cholestasis or liver failure, liver transplantation has long been regarded as the definitive therapy to address the hepatic crisis but does not offer a cure. Previous studies have reported that intravenous hemin/hematin may benefit some EPP patients, while the efficacy of intravenous heme arginate in treating EPP remains unreported. We report a 24-year-old male with EPP and severe cholestasis. From 2017 to 2024, the patient was hospitalized eight times for recurrent episodes of jaundice and abdominal pain. These symptoms were effectively alleviated through a comprehensive treatment including artificial liver support (PE + DPMAS), hepatoprotective therapy, and high-glucose infusion. During his latest hospitalization in 2025, artificial liver support failed to improve the liver dysfunction, leading to progressive deterioration to liver failure. Notably, after two doses of intravenous heme arginate, the total bilirubin level gradually declined with significant improvement of ascites, coagulation dysfunction and neuropsychiatric symptoms. The patient was discharged with hepatoprotective therapy and light avoidance with no recurrence at 6-month follow-up. This case suggests that intravenous heme arginate may provide clinical benefit in patients with EPP-associated liver failure and contributes to the limited literature supporting heme-based therapy in treating EPP hepatic crisis.
proteins
2026-09-04 | ‘Millions of superheated needles’: a patient’s experience of erythropoietic protoporphyria
We explore the profound physical and psychosocial burden of erythropoietic protoporphyria, which is characterized by agonizing phototoxic reactions described as ‘millions of superheated needles’. Through a personal account of diagnostic delays and the life-changing impact of a clinical trial for afamelanotide, we highlight the urgent need for equitable paediatric access to emerging therapies to mitigate the lifelong ‘invisible’ burden of this disease.
2026-03-07 | Afamelanotide improves quality of life and light tolerance in Austrian erythropoietic protoporphyria patients.
Erythropoietic protoporphyria (EPP) is a rare genetic disorder characterized by severe phototoxic reactions that occur within minutes of light exposure. In clinical studies, afamelanotide has been shown to prolong pain-free sun exposure, improve quality of life, and reduce the frequency and severity of phototoxic reactions. To present the real-world data of the Austrian EPP cohort treated with afamelanotide. Data from all Austrian EPP patients treated with afamelanotide in 2023 (n = 20) were analyzed and compared to baseline data on quality of life, phototoxic burn tolerance time (PBTT), reported UV index on the day with the longest PBTT, and incidence and severity of phototoxic reactions. Before treatment, the EPP QoL score had a median of 11.11 (IQR 3.03-19.44) and increased to a median of 79.17 (IQR 75.00-97.22) under therapy. Phototoxic burn tolerance time (PBTT) increased from a median of 15 minutes (IQR 10-25) to a median of 250 minutes (IQR 120-300) under therapy. Before therapy 88% of patients had phototoxic reactions, while on therapy only 33% were affected. Treatment side effects were only mild and transient. The real-world data of the Austrian cohort confirm the effectiveness and safety of afamelanotide in EPP patients.
2026-01-18 | Investigation of the stability profile of therapeutic α-MSH analogue: Insights from liquid chromatography-high resolution mass spectrometry analysis of afamelanotide.
Afamelanotide, also known as melanotan-1, is a synthetic 13-amino acid peptidomimetic of α-melanocyte stimulating hormone (α-MSH), and is a critical peptide orphan drug used for the management of erythropoietic protoporphyria. It contains norleucine and D-phenylalanine at positions 4 and 7, in place of methionine and L-phenylalanine, respectively as found in endogenous peptide. Therapeutic peptide stability profiling is crucial in drug development because chemical and physical degradation during storage alters structural properties, potentially reducing efficacy and compromising safety by preventing target engagement. Stability testing for synthetic peptides is performed by following the International Council for Harmonisation (ICH) guidelines Q1A(R2) and Q5C. The current work endeavours to explore afamelanotide's degradation pathways under various chemical and physical stress conditions: acidic, basic, neutral, and oxidative stress, UV light exposure, and increased temperature at 60⁰C. The study demonstrated that afamelanotide undergoes degradation under all applied stress conditions with the generation of fourteen different degradation products (DPs) which were separated by gradient reversed-phase HPLC on a Zorbax SB C18 column (300 Å, 4.6*150 mm, 3.5 µm) and the method was validated according to the ICH Q2(R1) guideline. To enable comprehensive characterization, the analysis was coupled with ultra-high-performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-HRMS/MS), where collision-induced dissociation yielded abundant and accurate fragmentation patterns, enabling the detailed structural elucidation of the products. While this work has identified several degradation pathways such as truncation, methylation, deacetylation, and oxidation, it also establishes complete stability profile of α-MSH analogue, thus offering key insights for the rational design of robust drug formulations.
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.
cell therapies
2026-06-23 | Early-Onset Severe Liver Fibrosis in a Toddler with Erythropoietic Protoporphyria Associated with Rare Compound Heterozygous FECH Variants.
Erythropoietic Protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis caused by pathogenic variants in FECH. Although most patients present with cutaneous photosensitivity in childhood, clinically significant liver disease is uncommon, and severe fibrosis in early childhood is rarely reported. A 2-year-old girl presented with recurrent photosensitivity and erythematous swelling after sun exposure. Laboratory evaluation revealed markedly elevated erythrocyte protoporphyrin (2406 µg/dL) and elevated plasma protoporphyrin. Genetic testing identified compound heterozygous FECH variants: c.901_902del (p.Trp301Alafs*23) and c.801G>A (p.Met267Ile). Liver enzymes were significantly elevated. Following liver biopsy demonstrated stage 3 bridging fibrosis with crystalline deposits in hepatocytes consistent with protoporphyric hepatopathy. The patient subsequently underwent hematopoietic stem cell transplantation with improvement of protoporphyrin levels and liver enzymes. However, the post-transplant course was complicated by severe infections, acute respiratory distress syndrome, and multiorgan failure, resulting in death. This case highlights rapidly progressive liver fibrosis in a toddler with EPP and emphasizes the importance of early hepatic monitoring in pediatric patients with markedly elevated protoporphyrin levels and rare FECH variants.
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.
2025-02-05 | Case of Rapid Progression of Liver Damage in a Patient with Erythropoietic Protoporphyria Accompanied with Bicuspid Aortic Valve
We encountered a patient who was diagnosed as having erythropoietic protoporphyria (EPP) and bicuspid aortic valve, in whom liver damage worsened within a short period until the development of liver cirrhosis. We investigated the progression of his liver pathology, including an autopsy. Liver biopsy demonstrated that the patient was already in a pre-cirrhotic stage (particularly pericellular) at a young age, which was caused by the accumulation of protoporphyrin. Electron microscopy findings and Iron staining revealed mitochondrial dysfunction and the involvement of iron. From these findings, we concluded that early control of this patient’s diseases, such as bone marrow transplantation and/or cardiac surgery before liver damage may have been effective.
2024-03-05 | A case of erythrogenic protoporphyria with thyrotoxicosis and liver dysfunction in an adult female.
Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the FECH gene, and it is inherited in an autosomal recessive manner. EPP usually produces acute pain photosensitivity after exposure to sunlight in infancy or early childhood, and liver failure is the most serious associated complication. This article reported an adult female case of EPP complicated with thyrotoxicosis and liver dysfunction which is a rare condition. The patient's liver function improved after liver protection treatment, her thyroid function returned to normal, and her EPP symptoms improved significantly. Moreover, the c.286C>T gene mutation may be the pathogenic locus of EPP. For patients with abnormal liver function, the possibility of EPP should be considered after the common causes are excluded, and FECH gene detection should be done to confirm the diagnosis in time. When EPP is associated with thyrotoxicosis and liver dysfunction, priority may be given to hepatoprotective therapy. 红细胞生成性原卟啉病(erythropoietic protoporphyria，EPP)是一种亚铁螯合酶(ferrochelatase，FECH)基因编码的FECH缺乏引起的遗传性代谢性疾病，以常染色体隐性遗传方式遗传。EPP通常在婴儿期或幼儿期暴露于阳光后产生急性疼痛光敏性，肝功能衰竭是最严重的并发症。本文报告１例成年女性EPP合并甲状腺功能亢进症(以下简称“甲亢”)及肝功能障碍的病例，临床上较为罕见。患者经保肝治疗后肝功能改善，甲状腺功能恢复正常，EPP症状明显改善。此外，c.286C>T基因突变可能是EPP的致病位点。对于肝功能异常患者，在排除常见病因后，应考虑EPP的可能，及时完善FECH基因检测确诊。当EPP合并甲亢和肝功能障碍时，可优先考虑保肝治疗。. Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the FECH gene, and it is inherited in an autosomal recessive manner. EPP usually produces acute pain photosensitivity after exposure to sunlight in infancy or early childhood, and liver failure is the most serious associated complication. This article reported an adult female case of EPP complicated with thyrotoxicosis and liver dysfunction which is a rare condition. The patient’s liver function improved after liver protection treatment, her thyroid function returned to normal, and her EPP symptoms improved significantly. Moreover, the c.286C>T gene mutation may be the pathogenic locus of EPP. For patients with abnormal liver function, the possibility of EPP should be considered after the common causes are excluded, and FECH gene detection should be done to confirm the diagnosis in time. When EPP is associated with thyrotoxicosis and liver dysfunction, priority may be given to hepatoprotective therapy.
oligonucleotides
2025-01-01 | Design and Application of Therapeutic Oligonucleotides for Targeted Delivery in A New Mouse Model of Erythropoietic Protoporphyria
On a global scale, rare diseases are anything but rare, with estimates seeing up to 6% of the world population collectively affected by a disorder classified as a rare disease. Rare diseases are often neglected by pharmaceutical manufacturers for low economic incentives due to small patient populations and high research and development costs. Within the last two decades, oligonucleotide therapeutics have rapidly established themselves as highly effective drugs for genetic disorders, particularly in the rare disease field; enabled by their rapid development, and well characterised safety profiles. While early development is often facile, challenges arise preclinically due to poor pharmacokinetic and pharmacodynamic performance in vivo. Several approved oligonucleotide therapeutics have successfully used chemical conjugation to harness receptor-mediated, targeted delivery and cellular uptake to overcome these challenges. Erythropoietic Protoporphyria (EPP) is a rare genetic disorder of heme synthesis. It is characterised by an accumulation of the heme precursor protoporphyrin nine (PPIX) leading to acute phototoxic reactions after exposure to sunlight. A majority of EPP cases can be linked to a single nucleotide polymorphism in intron 3 of the Ferrochelatase (FECH) pre-mRNA. This c.315-48 T > C variant promotes the use of an otherwise cryptic, aberrant splice site. The resulting mature mRNA is degraded by nonsense mediated decay (NMD), resulting in lower levels of FECH enzyme and the subsequent accumulation of excess PPIX. Previous work has identified a splice-switching oligonucleotide (SSO) able to mask the cryptic splice site and shift the splicing pattern towards the healthy FECH transcript. Here we describe the generation of a new mouse model of EPP by generating a transgenic line carrying a humanised FECH gene including the disease-associated polymorphism. Our model reproduces the human splicing defect and mimics both the human biochemistry and haematology, but does not exhibit the characteristic phototoxic phenotype. We employed this new model to evaluate a transferrin-receptor (TfR) targeting conjugate of the lead SSO for the delivery in vivo. We demonstrate increased uptake into the bone marrow and de-targeting off the liver. We observe significant improvements in splicing pattern and whole-blood PPIX levels under some treatment conditions, but were unable to demonstrate a therapeutic benefit across all parameters. The work presented here provides a solid platform for basic and medical research on EPP contributes to the pursuit of unlocking delivery of oligonucleotide therapeutics into a wider range of tissues beyond the liver.
2023-10-17 | Peptide Conjugates of a 2'-O-Methoxyethyl Phosphorothioate Splice-Switching Oligonucleotide Show Increased Entrapment in Endosomes.
Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid molecules that alter gene expression. However, their transport into appropriate cellular compartments is a limiting factor in their potency. Here, we synthesized splice-switching oligonucleotides (SSOs) previously developed to treat the rare disease erythropoietic protoporphyria. Using chemical ligation-quantitative polymerase chain reaction (CL-qPCR), we quantified the SSOs in cells and subcellular compartments following free uptake. To drive nuclear localization, we covalently conjugated nuclear localization signal (NLS) peptides to a lead 2'-O-methoxyethyl phosphorothioate SSO using thiol-maleimide chemistry. The conjugates and parent SSO displayed similar RNA target-binding affinities. CL-qPCR quantification of the conjugates in cells and subcellular compartments following free uptake revealed one conjugate with better nuclear accumulation relative to the parent SSO. However, compared to the parent SSO, which altered the splicing of the target pre-mRNA, the conjugates were inactive at splice correction under free uptake conditions in vitro. Splice-switching activity could be conferred on the conjugates by delivering them into cells via cationic lipid-mediated transfection or by treating the cells into which the conjugates had been freely taken up with chloroquine, an endosome-disrupting agent. Our results identify the major barrier to the activity of the peptide-oligonucleotide conjugates as endosomal entrapment.
2020-02-15 | Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria
ABSTRACT Erythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase ( FECH ) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation in trans to an allele bearing a SNP that favours aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.
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.
2019-02-01 | Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria
Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P1-9R) including a TFR1-targeting peptide coupled to a nine-arginine cell-penetrating peptide (CPP) that facilitates the release of the AON from TFR1 in endosomal vesicles. We demonstrated that the P1-9R/V1 nanocomplex promotes the efficient and prolonged redirection of splicing towards the physiological splice site and subsequent normalization of WT FECH mRNA and protein levels. Finally, the P1-9R/V1 nanocomplex increases WT FECH mRNA production and significantly decreases PPIX accumulation in primary cultures of differentiating erythroid progenitors from an overt EPP-affected individual. P1-9R is a method designed to target erythroid progenitors and represents a potentially powerful tool for the in vivo delivery of therapeutic DNA in many erythroid disorders.
small molecules
2026-09-06 | Review of the European Society for Photodynamic Therapy (Euro-PDT) Annual Congress 2025.
This article reviews novel data presented at the 2025 Annual Congress of the European Society for Photodynamic Therapy (Euro-PDT). Photodynamic therapy (PDT) has been investigated for the treatment of a broad spectrum of neoplastic, infectious and inflammatory dermatoses. PDT remains an effective treatment for actinic keratoses/field cancerization with increased interest in delivery of treatment indoors using artificial daylight sources as well as in home-administered daylight PDT. Sustained clearance has remained an important marker of the success of PDT for superficial and thin nodular basal cell carcinomas and updated data is presented. New studies confirm the potential for wider use of PDT for bacterial, fungal, and viral infections, including refractory cutaneous and mucosal warts, with encouraging results also in the treatment of necrobiosis lipoidica and erythropoietic protoporphyria.
2026-09-04 | Seasonal variations in erythropoietic protoporphyria patients' responses about sun behaviour, symptoms, and treatment effect.
Patients with erythropoietic protoporphyria (EPP) have highly variable, increased levels of erythrocyte protoporphyrin IX (PpIX). Upon exposure to visible light, the PpIX is released from the erythrocytes to the skin, producing phototoxic reactions. Severe photosensitivity heavily impacts the patients' daily behavior regarding sun exposure and outdoor life. As patients with EPP in Northern European countries may be free of symptoms during winter, their individual evaluation of sun behavior in summer, the severity of summer symptoms, and effect of oral treatment with Cimetidine and/or zinc sulphate may vary greatly depending on season when answering our EPP DLQI questionnaire. Nineteen patients with EPP answered questions in both mid-summer and the following mid-winter, respectively. The patients' sun behavior was identical when asked both summer and winter. Symptoms were reported as worse in winter than in summer. Treatment effect on symptoms was reported as better in summer than recalled when patients were asked the same question in winter. Erythrocyte PpIX decreased by 14 µmol/L during treatment. These observations may help the clinician decide when to schedule follow-up consultations for patients with EPP.
2026-08-20 | Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
2026-07-30 | An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
2026-05-11 | Heme arginate improves acute liver failure secondary to erythropoietic protoporphyria: a case report.
Erythropoietic protoporphyria (EPP) is a rare inherited disorder with limited therapeutic options. For EPP patients with advanced cholestasis or liver failure, liver transplantation has long been regarded as the definitive therapy to address the hepatic crisis but does not offer a cure. Previous studies have reported that intravenous hemin/hematin may benefit some EPP patients, while the efficacy of intravenous heme arginate in treating EPP remains unreported. We report a 24-year-old male with EPP and severe cholestasis. From 2017 to 2024, the patient was hospitalized eight times for recurrent episodes of jaundice and abdominal pain. These symptoms were effectively alleviated through a comprehensive treatment including artificial liver support (PE + DPMAS), hepatoprotective therapy, and high-glucose infusion. During his latest hospitalization in 2025, artificial liver support failed to improve the liver dysfunction, leading to progressive deterioration to liver failure. Notably, after two doses of intravenous heme arginate, the total bilirubin level gradually declined with significant improvement of ascites, coagulation dysfunction and neuropsychiatric symptoms. The patient was discharged with hepatoprotective therapy and light avoidance with no recurrence at 6-month follow-up. This case suggests that intravenous heme arginate may provide clinical benefit in patients with EPP-associated liver failure and contributes to the limited literature supporting heme-based therapy in treating EPP hepatic crisis.
proteins
2026-09-04 | ‘Millions of superheated needles’: a patient’s experience of erythropoietic protoporphyria
We explore the profound physical and psychosocial burden of erythropoietic protoporphyria, which is characterized by agonizing phototoxic reactions described as ‘millions of superheated needles’. Through a personal account of diagnostic delays and the life-changing impact of a clinical trial for afamelanotide, we highlight the urgent need for equitable paediatric access to emerging therapies to mitigate the lifelong ‘invisible’ burden of this disease.
2026-03-07 | Afamelanotide improves quality of life and light tolerance in Austrian erythropoietic protoporphyria patients.
Erythropoietic protoporphyria (EPP) is a rare genetic disorder characterized by severe phototoxic reactions that occur within minutes of light exposure. In clinical studies, afamelanotide has been shown to prolong pain-free sun exposure, improve quality of life, and reduce the frequency and severity of phototoxic reactions. To present the real-world data of the Austrian EPP cohort treated with afamelanotide. Data from all Austrian EPP patients treated with afamelanotide in 2023 (n = 20) were analyzed and compared to baseline data on quality of life, phototoxic burn tolerance time (PBTT), reported UV index on the day with the longest PBTT, and incidence and severity of phototoxic reactions. Before treatment, the EPP QoL score had a median of 11.11 (IQR 3.03-19.44) and increased to a median of 79.17 (IQR 75.00-97.22) under therapy. Phototoxic burn tolerance time (PBTT) increased from a median of 15 minutes (IQR 10-25) to a median of 250 minutes (IQR 120-300) under therapy. Before therapy 88% of patients had phototoxic reactions, while on therapy only 33% were affected. Treatment side effects were only mild and transient. The real-world data of the Austrian cohort confirm the effectiveness and safety of afamelanotide in EPP patients.
2026-01-18 | Investigation of the stability profile of therapeutic α-MSH analogue: Insights from liquid chromatography-high resolution mass spectrometry analysis of afamelanotide.
Afamelanotide, also known as melanotan-1, is a synthetic 13-amino acid peptidomimetic of α-melanocyte stimulating hormone (α-MSH), and is a critical peptide orphan drug used for the management of erythropoietic protoporphyria. It contains norleucine and D-phenylalanine at positions 4 and 7, in place of methionine and L-phenylalanine, respectively as found in endogenous peptide. Therapeutic peptide stability profiling is crucial in drug development because chemical and physical degradation during storage alters structural properties, potentially reducing efficacy and compromising safety by preventing target engagement. Stability testing for synthetic peptides is performed by following the International Council for Harmonisation (ICH) guidelines Q1A(R2) and Q5C. The current work endeavours to explore afamelanotide's degradation pathways under various chemical and physical stress conditions: acidic, basic, neutral, and oxidative stress, UV light exposure, and increased temperature at 60⁰C. The study demonstrated that afamelanotide undergoes degradation under all applied stress conditions with the generation of fourteen different degradation products (DPs) which were separated by gradient reversed-phase HPLC on a Zorbax SB C18 column (300 Å, 4.6*150 mm, 3.5 µm) and the method was validated according to the ICH Q2(R1) guideline. To enable comprehensive characterization, the analysis was coupled with ultra-high-performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-HRMS/MS), where collision-induced dissociation yielded abundant and accurate fragmentation patterns, enabling the detailed structural elucidation of the products. While this work has identified several degradation pathways such as truncation, methylation, deacetylation, and oxidation, it also establishes complete stability profile of α-MSH analogue, thus offering key insights for the rational design of robust drug formulations.
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.
cell therapies
2026-06-23 | Early-Onset Severe Liver Fibrosis in a Toddler with Erythropoietic Protoporphyria Associated with Rare Compound Heterozygous FECH Variants.
Erythropoietic Protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis caused by pathogenic variants in FECH. Although most patients present with cutaneous photosensitivity in childhood, clinically significant liver disease is uncommon, and severe fibrosis in early childhood is rarely reported. A 2-year-old girl presented with recurrent photosensitivity and erythematous swelling after sun exposure. Laboratory evaluation revealed markedly elevated erythrocyte protoporphyrin (2406 µg/dL) and elevated plasma protoporphyrin. Genetic testing identified compound heterozygous FECH variants: c.901_902del (p.Trp301Alafs*23) and c.801G>A (p.Met267Ile). Liver enzymes were significantly elevated. Following liver biopsy demonstrated stage 3 bridging fibrosis with crystalline deposits in hepatocytes consistent with protoporphyric hepatopathy. The patient subsequently underwent hematopoietic stem cell transplantation with improvement of protoporphyrin levels and liver enzymes. However, the post-transplant course was complicated by severe infections, acute respiratory distress syndrome, and multiorgan failure, resulting in death. This case highlights rapidly progressive liver fibrosis in a toddler with EPP and emphasizes the importance of early hepatic monitoring in pediatric patients with markedly elevated protoporphyrin levels and rare FECH variants.
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.
2025-02-05 | Case of Rapid Progression of Liver Damage in a Patient with Erythropoietic Protoporphyria Accompanied with Bicuspid Aortic Valve
We encountered a patient who was diagnosed as having erythropoietic protoporphyria (EPP) and bicuspid aortic valve, in whom liver damage worsened within a short period until the development of liver cirrhosis. We investigated the progression of his liver pathology, including an autopsy. Liver biopsy demonstrated that the patient was already in a pre-cirrhotic stage (particularly pericellular) at a young age, which was caused by the accumulation of protoporphyrin. Electron microscopy findings and Iron staining revealed mitochondrial dysfunction and the involvement of iron. From these findings, we concluded that early control of this patient’s diseases, such as bone marrow transplantation and/or cardiac surgery before liver damage may have been effective.
2024-03-05 | A case of erythrogenic protoporphyria with thyrotoxicosis and liver dysfunction in an adult female.
Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the FECH gene, and it is inherited in an autosomal recessive manner. EPP usually produces acute pain photosensitivity after exposure to sunlight in infancy or early childhood, and liver failure is the most serious associated complication. This article reported an adult female case of EPP complicated with thyrotoxicosis and liver dysfunction which is a rare condition. The patient's liver function improved after liver protection treatment, her thyroid function returned to normal, and her EPP symptoms improved significantly. Moreover, the c.286C>T gene mutation may be the pathogenic locus of EPP. For patients with abnormal liver function, the possibility of EPP should be considered after the common causes are excluded, and FECH gene detection should be done to confirm the diagnosis in time. When EPP is associated with thyrotoxicosis and liver dysfunction, priority may be given to hepatoprotective therapy. 红细胞生成性原卟啉病(erythropoietic protoporphyria，EPP)是一种亚铁螯合酶(ferrochelatase，FECH)基因编码的FECH缺乏引起的遗传性代谢性疾病，以常染色体隐性遗传方式遗传。EPP通常在婴儿期或幼儿期暴露于阳光后产生急性疼痛光敏性，肝功能衰竭是最严重的并发症。本文报告１例成年女性EPP合并甲状腺功能亢进症(以下简称“甲亢”)及肝功能障碍的病例，临床上较为罕见。患者经保肝治疗后肝功能改善，甲状腺功能恢复正常，EPP症状明显改善。此外，c.286C>T基因突变可能是EPP的致病位点。对于肝功能异常患者，在排除常见病因后，应考虑EPP的可能，及时完善FECH基因检测确诊。当EPP合并甲亢和肝功能障碍时，可优先考虑保肝治疗。. Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the FECH gene, and it is inherited in an autosomal recessive manner. EPP usually produces acute pain photosensitivity after exposure to sunlight in infancy or early childhood, and liver failure is the most serious associated complication. This article reported an adult female case of EPP complicated with thyrotoxicosis and liver dysfunction which is a rare condition. The patient’s liver function improved after liver protection treatment, her thyroid function returned to normal, and her EPP symptoms improved significantly. Moreover, the c.286C>T gene mutation may be the pathogenic locus of EPP. For patients with abnormal liver function, the possibility of EPP should be considered after the common causes are excluded, and FECH gene detection should be done to confirm the diagnosis in time. When EPP is associated with thyrotoxicosis and liver dysfunction, priority may be given to hepatoprotective therapy.
oligonucleotides
2025-01-01 | Design and Application of Therapeutic Oligonucleotides for Targeted Delivery in A New Mouse Model of Erythropoietic Protoporphyria
On a global scale, rare diseases are anything but rare, with estimates seeing up to 6% of the world population collectively affected by a disorder classified as a rare disease. Rare diseases are often neglected by pharmaceutical manufacturers for low economic incentives due to small patient populations and high research and development costs. Within the last two decades, oligonucleotide therapeutics have rapidly established themselves as highly effective drugs for genetic disorders, particularly in the rare disease field; enabled by their rapid development, and well characterised safety profiles. While early development is often facile, challenges arise preclinically due to poor pharmacokinetic and pharmacodynamic performance in vivo. Several approved oligonucleotide therapeutics have successfully used chemical conjugation to harness receptor-mediated, targeted delivery and cellular uptake to overcome these challenges. Erythropoietic Protoporphyria (EPP) is a rare genetic disorder of heme synthesis. It is characterised by an accumulation of the heme precursor protoporphyrin nine (PPIX) leading to acute phototoxic reactions after exposure to sunlight. A majority of EPP cases can be linked to a single nucleotide polymorphism in intron 3 of the Ferrochelatase (FECH) pre-mRNA. This c.315-48 T > C variant promotes the use of an otherwise cryptic, aberrant splice site. The resulting mature mRNA is degraded by nonsense mediated decay (NMD), resulting in lower levels of FECH enzyme and the subsequent accumulation of excess PPIX. Previous work has identified a splice-switching oligonucleotide (SSO) able to mask the cryptic splice site and shift the splicing pattern towards the healthy FECH transcript. Here we describe the generation of a new mouse model of EPP by generating a transgenic line carrying a humanised FECH gene including the disease-associated polymorphism. Our model reproduces the human splicing defect and mimics both the human biochemistry and haematology, but does not exhibit the characteristic phototoxic phenotype. We employed this new model to evaluate a transferrin-receptor (TfR) targeting conjugate of the lead SSO for the delivery in vivo. We demonstrate increased uptake into the bone marrow and de-targeting off the liver. We observe significant improvements in splicing pattern and whole-blood PPIX levels under some treatment conditions, but were unable to demonstrate a therapeutic benefit across all parameters. The work presented here provides a solid platform for basic and medical research on EPP contributes to the pursuit of unlocking delivery of oligonucleotide therapeutics into a wider range of tissues beyond the liver.
2023-10-17 | Peptide Conjugates of a 2'-O-Methoxyethyl Phosphorothioate Splice-Switching Oligonucleotide Show Increased Entrapment in Endosomes.
Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid molecules that alter gene expression. However, their transport into appropriate cellular compartments is a limiting factor in their potency. Here, we synthesized splice-switching oligonucleotides (SSOs) previously developed to treat the rare disease erythropoietic protoporphyria. Using chemical ligation-quantitative polymerase chain reaction (CL-qPCR), we quantified the SSOs in cells and subcellular compartments following free uptake. To drive nuclear localization, we covalently conjugated nuclear localization signal (NLS) peptides to a lead 2'-O-methoxyethyl phosphorothioate SSO using thiol-maleimide chemistry. The conjugates and parent SSO displayed similar RNA target-binding affinities. CL-qPCR quantification of the conjugates in cells and subcellular compartments following free uptake revealed one conjugate with better nuclear accumulation relative to the parent SSO. However, compared to the parent SSO, which altered the splicing of the target pre-mRNA, the conjugates were inactive at splice correction under free uptake conditions in vitro. Splice-switching activity could be conferred on the conjugates by delivering them into cells via cationic lipid-mediated transfection or by treating the cells into which the conjugates had been freely taken up with chloroquine, an endosome-disrupting agent. Our results identify the major barrier to the activity of the peptide-oligonucleotide conjugates as endosomal entrapment.
2020-02-15 | Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria
ABSTRACT Erythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase ( FECH ) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation in trans to an allele bearing a SNP that favours aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.
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.
2019-02-01 | Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria
Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P1-9R) including a TFR1-targeting peptide coupled to a nine-arginine cell-penetrating peptide (CPP) that facilitates the release of the AON from TFR1 in endosomal vesicles. We demonstrated that the P1-9R/V1 nanocomplex promotes the efficient and prolonged redirection of splicing towards the physiological splice site and subsequent normalization of WT FECH mRNA and protein levels. Finally, the P1-9R/V1 nanocomplex increases WT FECH mRNA production and significantly decreases PPIX accumulation in primary cultures of differentiating erythroid progenitors from an overt EPP-affected individual. P1-9R is a method designed to target erythroid progenitors and represents a potentially powerful tool for the in vivo delivery of therapeutic DNA in many erythroid disorders.
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Drug Discovery Landscape
2 orphan drug designations for Autosomal erythropoietic protoporphyria.
2 orphan drug designations for Autosomal erythropoietic protoporphyria.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
2-((3S,6S,12aS)-9-chloro-6-isobutyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-N,N-dimethylacetamide | small molecules | FDA | Portal Therapeutics, Inc. | |
L-cysteine | small molecules | FDA | Brigham and Women's Hospital |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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