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Blood Jun 2024X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in...
X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase, ALAS2, which encodes the first enzyme in heme biosynthesis. A related sideroblastic anemia is due to mutations in SLC25A38, which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited studies on the pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knock-in mouse models that recapitulate the main features of XLSA and XLPP, and, using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP porphyria, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ -thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases.
PubMed: 38900972
DOI: 10.1182/blood.2023023078 -
The British Journal of Dermatology Apr 2024Erythropoietic protoporphyria (EPP) patients experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that...
BACKGROUND
Erythropoietic protoporphyria (EPP) patients experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that 47-63% of EPP patients suffer from vitamin D deficiency and a high prevalence of osteoporosis. As of 2016 an effective treatment for EPP is available: the alpha-MSH analogue afamelanotide. So far studies on vitamin D levels in EPP have only investigated patients who were not treated with afamelanotide.
OBJECTIVES
To investigate the effects of afamelanotide treatment on vitamin D levels in EPP.
METHODS
A multi-centre observational cohort study, in adult patients with EPP from the Erasmus Medical Centre, the Netherlands and the University Hospital Düsseldorf, Germany. Routinely-collected vitamin D levels between 2005 and 2021 were used for analysis. Patient exposure to cholecalciferol or afamelanotide was categorized into four treatment groups; untreated, cholecalciferol, afamelanotide, and combined treatment. A linear mixed model for longitudinal data was applied to measure the effect of the treatment groups, compared to the untreated, on vitamin D levels.
RESULTS
A total of 230 patients and 1774 vitamin D measurements were included. Prevalence of vitamin D deficiency remained high despite afamelanotide treatment: <50 nmol/l in 71.8% of patients, and severe deficiency <30 nmol/l in 48.1%. Afamelanotide treatment alone did not lead to a significant average increase in vitamin D levels (β:0.5, 95% Confidence Interval [CI]: -3.2 - 4.2). In contrast, cholecalciferol and combined therapy with afamelanotide, led to a significant increase in vitamin D levels (β:11.6, CI: 7.2-15.9 and β:15.2, CI: 12.3-18.1).
CONCLUSION
Cholecalciferol remains essential for treatment of vitamin D deficiency in EPP, irrespective of new treatment options like afamelanotide. Afamelanotide treatment did not affect vitamin D levels. We suggest that future guidelines include continuous monitoring of vitamin D and prescription of cholecalciferol in all patients with EPP, including those treated with afamelanotide.
PubMed: 38634774
DOI: 10.1093/bjd/ljae148 -
Blood May 2024In this last decade, a deeper understanding of the pathophysiology of hereditary red cell disorders and the development of novel classes of pharmacologic agents have...
In this last decade, a deeper understanding of the pathophysiology of hereditary red cell disorders and the development of novel classes of pharmacologic agents have provided novel therapeutic approaches to thalassemias, sickle cell disease (SCD) and other red cell disorders. Here, we analyze and discuss the novel therapeutic options according to their targets and taking into consideration the complex process of erythroid differentiation, maturation, and survival of erythrocytes in the peripheral circulation. We focus on active clinical exploratory and confirmatory trials on thalassemias, SCD and other red cell disorders. Beside -thalassemia and SCD, we found that the development of new therapeutic strategies has allowed the design of clinic studies also for hereditary red cell disorders still lacking valuable therapeutic alternative such as -thalassemias, congenital dyserythropoietic anemia or Blackfan Diamond anemia. In addition, reduction of heme synthesis, which can be achieved by the repurposed anti-psychotic drug Bitopertin, might affect not only hematological disorders but multiorgan diseases such as erythropoietic protoporphyria. Finally, our review highlights the current state of therapeutic scenarios, in which multiple indications targeting different red cell disorders are being considered for a single agent. This is welcome change which will hopefully expand therapeutic option for patients affected by thalassemias, SCD and other red cell disorders.
PubMed: 38820588
DOI: 10.1182/blood.2023022193 -
Hematology, Transfusion and Cell Therapy Apr 2024
PubMed: 38719715
DOI: 10.1016/j.htct.2024.02.027 -
Hepatology (Baltimore, Md.) Mar 2024
Topics: Humans; Iron; Protoporphyria, Erythropoietic; Dietary Supplements
PubMed: 37862552
DOI: 10.1097/HEP.0000000000000633 -
Photodermatology, Photoimmunology &... Jul 2023
Topics: Humans; Protoporphyria, Erythropoietic; Elasticity Imaging Techniques; Liver Cirrhosis; Risk Factors; Obesity
PubMed: 36346074
DOI: 10.1111/phpp.12843 -
Clinical and Experimental Dermatology Jun 2024
PubMed: 38889221
DOI: 10.1093/ced/llae234 -
Biochemistry Jun 2024The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and...
The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and succinyl-CoA to yield aminolevulinic acid. In humans, the ALAS isoform responsible for heme production during red blood cell development is the erythroid-specific ALAS2 isoform. Owing to its essential role in erythropoiesis, changes in human ALAS2 (hALAS2) function can lead to two different blood disorders. X-linked sideroblastic anemia results from loss of ALAS2 function, while X-linked protoporphyria results from gain of ALAS2 function. Interestingly, mutations in the ALAS2 C-terminal extension can be implicated in both diseases. Here, we investigate the molecular basis for enzyme dysfunction mediated by two previously reported C-terminal loss-of-function variants, hALAS2 V562A and M567I. We show that the mutations do not result in gross structural perturbations, but the enzyme stability for V562A is decreased. Additionally, we show that enzyme stability moderately increases with the addition of the pyridoxal 5'-phosphate (PLP) cofactor for both variants. The variants display differential binding to PLP and the individual substrates compared to wild-type hALAS2. Although hALAS2 V562A is a more active enzyme , it is less efficient concerning succinyl-CoA binding. In contrast, the M567I mutation significantly alters the cooperativity of substrate binding. In combination with previously reported cell-based studies, our work reveals the molecular basis by which hALAS2 C-terminal mutations negatively affect ALA production necessary for proper heme biosynthesis.
PubMed: 38888931
DOI: 10.1021/acs.biochem.4c00066 -
Microbiology Spectrum Apr 2024Equid alphaherpesvirus 8 (EqHV-8) is one of the most economically important viruses that is known to cause severe respiratory disease, abortion, and neurological...
Equid alphaherpesvirus 8 (EqHV-8) is one of the most economically important viruses that is known to cause severe respiratory disease, abortion, and neurological syndromes in equines. However, no effective vaccines or therapeutic agents are available to control EqHV-8 infection. Heme oxygenase-1 (HO-1) is an antioxidant defense enzyme that displays significant cytoprotective effects against different viral infections. However, the literature on the function of HO-1 during EqHV-8 infection is little. We explored the effects of HO-1 on EqHV-8 infection and revealed its potential mechanisms. Our results demonstrated that HO-1 induced by cobalt-protoporphyrin (CoPP) or HO-1 overexpression inhibited EqHV-8 replication in susceptible cells. In contrast, HO-1 inhibitor (zinc protoporphyria) or siRNA targeting HO-1 reversed the anti-EqHV-8 activity. Furthermore, biliverdin, a metabolic product of HO-1, mediated the anti-EqHV-8 effect of HO-1 via both the protein kinase C (PKC)β/extracellular signal-regulated kinase (ERK)1/ERK2 and nitric oxide (NO)-dependent cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathways. In addition, CoPP protected the mice by reducing the EqHV-8 infection in the lungs. Altogether, these results indicated that HO-1 can be developed as a promising therapeutic strategy to control EqHV-8 infection.IMPORTANCEEqHV-8 infections have threatened continuously donkey and horse industry worldwide, which induces huge economic losses every year. However, no effective vaccination strategies or drug against EqHV-8 infection until now. Our present study found that one host protien HO-1 restrict EqHV-8 replication and . Furthermore, we demonstrate that HO-1 and its metabolite biliverdin suppress EqHV-8 relication via the PKCβ/ERK1/ERK2 and NO/cGMP/PKG pathways. Hence, we believe that HO-1 can be developed as a promising therapeutic strategy to control EqHV-8 infection.
Topics: Horses; Animals; Mice; Heme Oxygenase-1; Cyclic GMP-Dependent Protein Kinases; Biliverdine; Signal Transduction; Virus Replication
PubMed: 38441979
DOI: 10.1128/spectrum.03220-23 -
International Journal of Environmental... May 2024The National Institute for Health and Care Excellence (NICE) in England uses quality-adjusted life years (QALYs) to assess the cost-effectiveness of treatments. A QALY...
Fair Funding Decisions: Consistency of the Time Horizons Used in the Calculation of Quality-Adjusted Life Years for Therapies for Very Rare Diseases by the National Institute for Health and Care Excellence in England.
The National Institute for Health and Care Excellence (NICE) in England uses quality-adjusted life years (QALYs) to assess the cost-effectiveness of treatments. A QALY is a measure that combines the size of the clinical benefit of a treatment with the time the patient benefits from it, i.e., the time horizon. We wanted to know how consistently QALY gains are calculated at NICE. Therefore, we have analysed information on the time horizons used for the QALY calculations of the concluded evaluations conducted under the Highly Specialised Technologies programme for treatments of very rare diseases at NICE. For treatments with final guidance published by December 2023 ( = 29), a time horizon of median 97.5 years (range: 35 to 125 years) was used to calculate the QALY gains. For most QALY calculations, the accepted time horizon was longer than either the expected treatment duration or the estimated life expectancy. In contrast, for the only technology with a final negative funding decision, i.e., afamelanotide for treating the lifelong chronic disease erythropoietic protoporphyria, a time horizon that was shorter than the expected treatment duration was used. The fairness and consistency of the evaluation process of treatments for very rare diseases at NICE should be reviewed.
Topics: Rare Diseases; Quality-Adjusted Life Years; Humans; England; Cost-Benefit Analysis; Decision Making; Time Factors
PubMed: 38791830
DOI: 10.3390/ijerph21050616