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Herbert L. Bonkovsky - One of the best experts on this subject based on the ideXlab platform.

  • phase 3 trial of rnai therapeutic givosiran for acute intermittent porphyria
    The New England Journal of Medicine, 2020
    Co-Authors: Eliane Sardh, Montgomery D Bissell, Herbert L. Bonkovsky, David C Rees, Paolo Ventura, Paula Aguilera Peiro, Ulrich Stolzel, Jerzy Windyga, Karl E. Anderson
    Abstract:

    Abstract Background Up-regulation of hepatic delta-Aminolevulinic Acid Synthase 1 (ALAS1), with resultant accumulation of delta-Aminolevulinic Acid (ALA) and porphobilinogen, is central to the path...

  • strong correlation of ferrochelatase enzymatic activity with mitoferrin 1 mrna in lymphoblasts of patients with protoporphyria
    Molecular Genetics and Metabolism, 2019
    Co-Authors: John D Phillips, Karl E. Anderson, Herbert L. Bonkovsky, Manisha Balwani, Collin Farrell, Yongming Wang, Ashwani K Singal, Montgomery Bissell, Toni Seay, Barry H Paw
    Abstract:

    Abstract Accumulation of protoporphyrin IX (PPIX) and Zn-PPIX, are the clinical hallmarks of protoporphyria. Phenotypic expression of protoporphyria is due to decreased activity of ferrochelatase (FECH) or to increased activity of Aminolevulinic Acid Synthase (ALAS) in red blood cells. Other genetic defects have been shown to contribute to disease severity including loss of function mutations in the mitochondrial AAA-ATPase, CLPX and mutations in the Iron-responsive element binding protein 2 (IRP2), in mice. It is clear that multiple paths lead to a common phenotype of excess plasma PPIX that causes a phototoxic reaction on sun exposed areas. In this study we examined the association between mitochondrial iron acquisition and utilization with activity of FECH. Our data show that there is a metabolic link between the activity FECH and levels of MFRN1 mRNA. We examined the correlation between FECH activity and MFRN1 mRNA in cell lines established from patients with the classical protoporphyria, porphyria due to defects in ALAS2 mutations. Our data confirm MFRN1 message levels positively correlated with FECH enzymatic activity in all cell types.

  • phase 1 trial of an rna interference therapy for acute intermittent porphyria
    The New England Journal of Medicine, 2019
    Co-Authors: Eliane Sardh, John D Phillips, Penelope E Stein, David C Rees, Charles J Parker, Herbert L. Bonkovsky
    Abstract:

    Abstract Background Induction of delta Aminolevulinic Acid Synthase 1 (ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations...

  • porphyrias an overview and update for physicians and their staffs
    Medical research archives, 2017
    Co-Authors: Brandon Marion, Jared Rejeski, Sean Rudnick, Herbert L. Bonkovsky
    Abstract:

    AbstractHeme is an essential molecule involved in various biochemical processes in many species. It is used in the formation of cytochromes P-450, mitochondrial cytochromes, hemoproteins, catalase, peroxidase, myoglobin, and hemoglobin. Formation of the heme molecule involves a multistep process using eight enzymes. Biosynthesis of heme occurs in the mitochondria and in the cytoplasm. Most tissues in the human body synthesize heme, but the main sites of formation are in the bone marrow (erythroblasts) and in the liver (hepatocytes). Porphyrias are a unique group of disorders mainly due to inborn errors of metabolism of the heme synthetic pathway. The deficient activity of the enzymes can lead to a build-up of heme precursors, resulting in wide heterogeneity of clinical symptoms. To date, there are nine described porphyrias: Aminolevulinic Acid dehydratase deficient porphyria (ALADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLPP). The classification of porphyrias is based on    1) the main sites of heme precursor synthesis (hepatic, erythropoietic), 2) acute or chronic porphyria, and 3) cutaneous involvement. In this review, we focus on AIP, PCT, and EPP, the three most common forms of porphyria in the United States. A case vignette for each of the three is provided and followed by a discussion regarding the clinical features, pathogenesis, diagnosis/management, and prognosis of each. Management of AIP currently revolves around avoidance of drugs and chemicals and severe caloric deprivation, which may trigger acute attacks, and use of intravenous heme for acute attacks. Exciting new therapies, particularly siRNA to down regulate hepatic 5-Aminolevulinic Acid Synthase, are under active development. Management of EPP currently involves protection from sunlight, but implants of afamelanotide have shown good efficacy and are already approved by the European Medicines Agency.

  • advances in the management of erythropoietic protoporphyria role of afamelanotide
    The application of clinical genetics, 2016
    Co-Authors: Ashley M Lane, Jerome T Mckay, Herbert L. Bonkovsky
    Abstract:

    Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X-linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced quality of life. They are due to marked overproduction of protoporphyrin (PP) chiefly by erythroblasts and reticulocytes. In EPP, the underlying genetic defect is in the ferrochelatase gene, which encodes the final enzyme in the heme synthetic pathway. In XLPP, the genetic defect is a gain-of-function mutation, usually a four-base deletion, in the gene that encodes the enzyme 5-Aminolevulinic Acid Synthase-2, the first and rate-controlling enzyme of heme synthesis in developing red blood cells. The excess PP causes acute and painful photosensitivity, being activated by light in the long ultraviolet to blue spectrum (380-420 nm, the Soret band). Although several treatments have been proposed, presently no very effective treatment exists for EPP or XLPP. Afamelanotide (Scenesse®) is a first-in-class synthetic analog of α-melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. This paper provides a review of the clinical characteristics and current therapies for EPP/XLPP. We discuss the pharmacology, clinical efficacy, safety, and tolerability of afamelanotide and summarize the results of several key Phase II and III clinical trials. These data indicate that afamelanotide is a promising therapy for those with these debilitating diseases.

Urs A Meyer - One of the best experts on this subject based on the ideXlab platform.

  • Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug-responsive enhancer of the murine 5-Aminolevulinic Acid Synthase gene.
    The Journal of biological chemistry, 2003
    Co-Authors: David J. Fraser, Adrian Zumsteg, Urs A Meyer
    Abstract:

    Abstract Nuclear receptors have been implicated in the transcriptional regulation of expression of a growing number of genes, including cytochromes P450 and 5-aminolevulinate Synthase (ALAS1), the first and rate-limiting enzyme in the heme biosynthesis pathway. Although drugs that induce cytochromes P450 also induce ALAS1, the regulatory mechanisms governing these pathways have not been fully elucidated. We have identified a drug-responsive enhancer in the murine ALAS1 gene. This sequence mediates transcriptional activation by a wide range of compounds including typical cytochrome P450 pan-inducers phenobarbital and metyrapone, as well as specific activators of the pregnane X receptor and the constitutive androstane receptor. ALAS1 drug-responsive enhancer sequences were identified by transient transfection of reporter gene constructs in the drug-responsive leghorn male hepatoma cell line. Using the NUBIScan algorithm, DR4 nuclear receptor binding sites were identified within the elements and their roles in mediating transcriptional activation of ALAS1 were confirmed by site-directed mutagenesis. Electrophoretic mobility shift assays demonstrate clear interactions of mouse pregnane X receptor and constitutive androstane receptor on the ADRES. Transactivation assays in CV-1 cells implicate the nuclear receptors as major contributors to transcriptional activation of ALAS1. Moreover, in vivo studies in knock-out animals confirm the induction of ALAS1 is mediated at least in part by nuclear receptors. These studies are the first to explain drug induction via drug response elements for mammalian ALAS1.

  • Zinc mesoporphyrin represses induced hepatic 5-Aminolevulinic Acid Synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria
    Hepatology, 2001
    Co-Authors: Mace M Schuurmans, Francine Hoffmann, Raija L P Lindberg, Urs A Meyer
    Abstract:

    Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-Aminolevulinic Acid Synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 μmol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-Aminolevulinic Acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase–deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 μmol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study. (HEPATOLOGY 2001;33:1217-1222.)

  • porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria
    Nature Genetics, 1996
    Co-Authors: Raija L P Lindberg, Bernard Grandchamp, Catherine Porcher, Birgit Ledermann, Kurt Burki, Sebastian Brandner, Adriano Aguzzi, Urs A Meyer
    Abstract:

    Acute intermittent porphyria (AIP) is a human disease resulting from a dominantly inherited partial deficiency of the heme biosynthetic enzyme, porphobilinogen deaminase (PBGD). The frequency of the trait for AIP is 1/10,000 in most populations, but may be markedly higher (1/500) in psychiatric patients. The clinical expression of the disease is characterized by acute, life-threatening attacks of 'porphyric neuropathy' that include abdominal pain, motor and sensory neurological deficits and psychiatric symptoms. Attacks are frequently precipitated by drugs, alcohol and low caloric intake. Identical symptoms occur in other hepatic porphyrias. To study the pathogenesis of the neurologic symptoms of AIP we have generated Pbgd-deficient mice by gene targeting. These mice exhibit the typical biochemical characteristics of human AIP, notably, decreased hepatic Pbgd activity, increased delta-Aminolevulinic Acid Synthase activity and massively increased urinary excretion of the heme precursor, delta-Aminolevulinic Acid after treatment with drugs such as phenobarbital. Behavioural tests reveal decreased motor function and histopathological findings include axonal neuropathy and neurologic muscle atrophy.

John D Phillips - One of the best experts on this subject based on the ideXlab platform.

  • explore a prospective multinational natural history study of patients with acute hepatic porphyria with recurrent attacks
    Hepatology, 2020
    Co-Authors: Laurent Gouya, John D Phillips, Montgomery D Bissell, David C Rees, Paolo Ventura, Ulrich Stolzel, Manisha Balwani, Raili Kauppinen, Janneke G Langendonk, Robert J Desnick
    Abstract:

    textabstractBackground and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-Aminolevulinic Acid Synthase 1 messenger ribonucleic Acid levels, δ-Aminolevulinic Acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

  • strong correlation of ferrochelatase enzymatic activity with mitoferrin 1 mrna in lymphoblasts of patients with protoporphyria
    Molecular Genetics and Metabolism, 2019
    Co-Authors: John D Phillips, Karl E. Anderson, Herbert L. Bonkovsky, Manisha Balwani, Collin Farrell, Yongming Wang, Ashwani K Singal, Montgomery Bissell, Toni Seay, Barry H Paw
    Abstract:

    Abstract Accumulation of protoporphyrin IX (PPIX) and Zn-PPIX, are the clinical hallmarks of protoporphyria. Phenotypic expression of protoporphyria is due to decreased activity of ferrochelatase (FECH) or to increased activity of Aminolevulinic Acid Synthase (ALAS) in red blood cells. Other genetic defects have been shown to contribute to disease severity including loss of function mutations in the mitochondrial AAA-ATPase, CLPX and mutations in the Iron-responsive element binding protein 2 (IRP2), in mice. It is clear that multiple paths lead to a common phenotype of excess plasma PPIX that causes a phototoxic reaction on sun exposed areas. In this study we examined the association between mitochondrial iron acquisition and utilization with activity of FECH. Our data show that there is a metabolic link between the activity FECH and levels of MFRN1 mRNA. We examined the correlation between FECH activity and MFRN1 mRNA in cell lines established from patients with the classical protoporphyria, porphyria due to defects in ALAS2 mutations. Our data confirm MFRN1 message levels positively correlated with FECH enzymatic activity in all cell types.

  • results of a pilot study of isoniazid in patients with erythropoietic protoporphyria
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Charles J Parker, Karl E. Anderson, Manisha Balwani, Laurent Gouya, Robert J Desnick, Ashwani K Singal, Montgomery D Bissel, Joseph R Bloomer, Herve Puy, John D Phillips
    Abstract:

    Abstract Erythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinical phenotype. Aminolevulinic Acid Synthase 2 (ALAS2), the rate limiting enzyme of the heme pathway in the erythron, is a therapeutic target in EPP because inhibiting enzyme function would reduce downstream production of protoporphyrin IX (PPIX), preventing accumulation of the toxic molecule and thereby ameliorating symptoms. Isoniazid (INH) is widely used for treatment of latent and active M. tuberculosis (TB). Sideroblastic anemia is observed in some patients taking INH, and studies have shown that this process is a consequence of inhibition of ALAS2 by INH. Based on these observations, we postulated that INH might have therapeutic activity in patients with EPP. We challenged this hypothesis in a murine model of EPP and showed that, after 4 weeks of treatment with INH, both plasma PPIX and hepatic PPIX were significantly reduced. Next, we tested the effect of INH on patients with EPP. After eight weeks, no significant difference in plasma or red cell PPIX was observed among the 15 patients enrolled in the study. These results demonstrate that while INH can lower PPIX in an animal model of EPP, the standard dose used to treat TB is insufficient to affect levels in humans.

  • phase 1 trial of an rna interference therapy for acute intermittent porphyria
    The New England Journal of Medicine, 2019
    Co-Authors: Eliane Sardh, John D Phillips, Penelope E Stein, David C Rees, Charles J Parker, Herbert L. Bonkovsky
    Abstract:

    Abstract Background Induction of delta Aminolevulinic Acid Synthase 1 (ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations...

  • longitudinal analysis of erythrocyte and plasma protoporphyrin levels in patients with protoporphyria
    The journal of applied laboratory medicine, 2018
    Co-Authors: Eric Gou, Karl E. Anderson, Cindy Weng, Tom Greene, John D Phillips
    Abstract:

    Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited cutaneous porphyrias resulting from decreased activity of ferrochelatase and gain-of-function mutations of δ-Aminolevulinic Acid Synthase-2, respectively. Both of these protoporphyrias cause increased protoporphyrin levels that cause photosensitivity and may lead to hepatopathy and further increases in erythrocyte and plasma porphyrin levels. Methods: We evaluated erythrocyte protoporphyrin and plasma porphyrin levels in all subjects with EPP (83 subjects) or XLP (9 subjects) without evidence of liver disease tested repeatedly at a single laboratory over 25 years. Results: Intersubject variation contributed more than intrasubject variation (78.86% vs 21.14%) to overall variability, and longitudinal variability, estimated by CV, averaged 26%. Erythrocyte total protoporphyrin levels were similar in males and females with EPP (ratio, 0.99; 95% CI, 0.82–1.21; P = 0.96) but were higher in males than females with XLP, although this difference was not statistically significant (ratio, 0.76; 95% CI, 0.43–1.36; P = 0.35). Analysis of 20 subjects from 9 separate families showed significant effects of family compared with effects of individual variation on total variance (50% vs 25%; P Conclusion: Variation of erythrocyte total protoporphyrin up to 25% is expected in patients with protoporphyria, whereas greater increases might raise concern for protoporphyric hepatopathy.

Montgomery D Bissell - One of the best experts on this subject based on the ideXlab platform.

  • phase 3 trial of rnai therapeutic givosiran for acute intermittent porphyria
    The New England Journal of Medicine, 2020
    Co-Authors: Eliane Sardh, Montgomery D Bissell, Herbert L. Bonkovsky, David C Rees, Paolo Ventura, Paula Aguilera Peiro, Ulrich Stolzel, Jerzy Windyga, Karl E. Anderson
    Abstract:

    Abstract Background Up-regulation of hepatic delta-Aminolevulinic Acid Synthase 1 (ALAS1), with resultant accumulation of delta-Aminolevulinic Acid (ALA) and porphobilinogen, is central to the path...

  • explore a prospective multinational natural history study of patients with acute hepatic porphyria with recurrent attacks
    Hepatology, 2020
    Co-Authors: Laurent Gouya, John D Phillips, Montgomery D Bissell, David C Rees, Paolo Ventura, Ulrich Stolzel, Manisha Balwani, Raili Kauppinen, Janneke G Langendonk, Robert J Desnick
    Abstract:

    textabstractBackground and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-Aminolevulinic Acid Synthase 1 messenger ribonucleic Acid levels, δ-Aminolevulinic Acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

  • role of delta Aminolevulinic Acid in the symptoms of acute porphyria
    The American Journal of Medicine, 2015
    Co-Authors: Montgomery D Bissell, Jennifer C Lai, Raymond K Meister, Paul D Blanc
    Abstract:

    Abstract Background Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-Aminolevulinic Acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative. Methods We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome. Results Although each of these conditions has characteristic urine biochemistry, all exhibit excess delta-Aminolevulinic Acid. Moreover, in all, treatment with hemin reduces delta-Aminolevulinic Acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective. Conclusions There is now convincing evidence that delta-Aminolevulinic Acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-Aminolevulinic Acid Synthase-1, the enzyme that catalyzes delta-Aminolevulinic Acid formation. Delta-Aminolevulinic Acid Synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria.

Robert J Desnick - One of the best experts on this subject based on the ideXlab platform.

  • explore a prospective multinational natural history study of patients with acute hepatic porphyria with recurrent attacks
    Hepatology, 2020
    Co-Authors: Laurent Gouya, John D Phillips, Montgomery D Bissell, David C Rees, Paolo Ventura, Ulrich Stolzel, Manisha Balwani, Raili Kauppinen, Janneke G Langendonk, Robert J Desnick
    Abstract:

    textabstractBackground and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-Aminolevulinic Acid Synthase 1 messenger ribonucleic Acid levels, δ-Aminolevulinic Acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

  • EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
    'Wiley', 2020
    Co-Authors: Gouya L., Balwani M., Ventura P., Kauppinen R., Janneke G Langendonk, D.m. Bissell, J.d. Phillips, Dc Rees, Robert J Desnick
    Abstract:

    BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced 653 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic \u3b4-Aminolevulinic Acid Synthase 1 messenger ribonucleic Acid levels, \u3b4-Aminolevulinic Acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies

  • results of a pilot study of isoniazid in patients with erythropoietic protoporphyria
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Charles J Parker, Karl E. Anderson, Manisha Balwani, Laurent Gouya, Robert J Desnick, Ashwani K Singal, Montgomery D Bissel, Joseph R Bloomer, Herve Puy, John D Phillips
    Abstract:

    Abstract Erythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinical phenotype. Aminolevulinic Acid Synthase 2 (ALAS2), the rate limiting enzyme of the heme pathway in the erythron, is a therapeutic target in EPP because inhibiting enzyme function would reduce downstream production of protoporphyrin IX (PPIX), preventing accumulation of the toxic molecule and thereby ameliorating symptoms. Isoniazid (INH) is widely used for treatment of latent and active M. tuberculosis (TB). Sideroblastic anemia is observed in some patients taking INH, and studies have shown that this process is a consequence of inhibition of ALAS2 by INH. Based on these observations, we postulated that INH might have therapeutic activity in patients with EPP. We challenged this hypothesis in a murine model of EPP and showed that, after 4 weeks of treatment with INH, both plasma PPIX and hepatic PPIX were significantly reduced. Next, we tested the effect of INH on patients with EPP. After eight weeks, no significant difference in plasma or red cell PPIX was observed among the 15 patients enrolled in the study. These results demonstrate that while INH can lower PPIX in an animal model of EPP, the standard dose used to treat TB is insufficient to affect levels in humans.

  • EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
    'Wiley', 2019
    Co-Authors: Laurent Gouya, David C Rees, Paolo Ventura, Ulrich Stolzel, Raili Kauppinen, Janneke G Langendonk, M. Balwani, D.m. Bissell, J.d. Phillips, Robert J Desnick
    Abstract:

    Background and Aims Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced >= 3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic delta-Aminolevulinic Acid Synthase 1 messenger ribonucleic Acid levels, delta-Aminolevulinic Acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies