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17 pages, 4407 KiB

Open AccessFeature PaperArticle

The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models

by Pedro Besada, María Gallardo-Gómez, Tania Pérez-Márquez, Lucía Patiño-Álvarez, Sergio Pantano, Carlos Silva-López, Carmen Terán, Ana Arévalo-Gómez, Aurora Ruz-Zafra, Julián Fernández-Martín and Saida Ortolano

Biomolecules 2021, 11(12), 1856; https://doi.org/10.3390/biom11121856 - 10 Dec 2021

Cited by 1 | Viewed by 3420

Abstract

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone [...] Read more.

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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12 pages, 2674 KiB

Open AccessArticle

Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation

by Erika Rimondi, Erica Valencic, Alberto Tommasini, Paola Secchiero, Elisabetta Melloni and Annalisa Marcuzzi

Biomolecules 2021, 11(10), 1438; https://doi.org/10.3390/biom11101438 - 30 Sep 2021

Cited by 2 | Viewed by 2945

Abstract

Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do [...] Read more.

Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD’s mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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11 pages, 1135 KiB

Open AccessArticle

Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients

by Katalin Koczok, László Horváth, Zeljka Korade, Zoltán András Mezei, Gabriella P. Szabó, Ned A. Porter, Eszter Kovács, Károly Mirnics and István Balogh

Biomolecules 2021, 11(8), 1228; https://doi.org/10.3390/biom11081228 - 17 Aug 2021

Cited by 3 | Viewed by 3307

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated [...] Read more.

Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low–normal plasma vitamin E concentrations (7.19–15.68 μmol/L), while vitamin A concentrations were found to be normal or high (1.26–2.68 μmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2–0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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Review

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14 pages, 538 KiB

Open AccessEditor’s ChoiceReview

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

by Mariangela Succoio, Rosa Sacchettini, Alessandro Rossi, Giancarlo Parenti and Margherita Ruoppolo

Biomolecules 2022, 12(7), 968; https://doi.org/10.3390/biom12070968 - 11 Jul 2022

Cited by 29 | Viewed by 18688

Abstract

Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of [...] Read more.

Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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11 pages, 812 KiB

Open AccessEditor’s ChoiceReview

CPLANE Complex and Ciliopathies

by Jesús Eduardo Martín-Salazar and Diana Valverde

Biomolecules 2022, 12(6), 847; https://doi.org/10.3390/biom12060847 - 17 Jun 2022

Cited by 13 | Viewed by 2819

Abstract

Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some [...] Read more.

Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial–digital syndrome (OFDS) and Bardet–Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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19 pages, 1084 KiB

Open AccessFeature PaperReview

Therapeutic Approaches in Lysosomal Storage Diseases

by Carlos Fernández-Pereira, Beatriz San Millán-Tejado, María Gallardo-Gómez, Tania Pérez-Márquez, Marta Alves-Villar, Cristina Melcón-Crespo, Julián Fernández-Martín and Saida Ortolano

Biomolecules 2021, 11(12), 1775; https://doi.org/10.3390/biom11121775 - 26 Nov 2021

Cited by 38 | Viewed by 5475

Abstract

Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme [...] Read more.

Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme replacement therapy, gene therapy, or small molecules have been approved or are under clinical development to treat lysosomal storage disorders. The present article reviews the main therapeutic strategies that have been proposed so far, highlighting possible limitations and future perspectives. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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12 pages, 1141 KiB

Open AccessEditor’s ChoiceReview

Osteogenesis Imperfecta: Current and Prospective Therapies

by Malwina Botor, Agnieszka Fus-Kujawa, Marta Uroczynska, Karolina L. Stepien, Anna Galicka, Katarzyna Gawron and Aleksander L. Sieron

Biomolecules 2021, 11(10), 1493; https://doi.org/10.3390/biom11101493 - 10 Oct 2021

Cited by 42 | Viewed by 12376

Abstract

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a [...] Read more.

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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23 pages, 1360 KiB

Open AccessReview

Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments

by Andrea Güémez and Elisa García

Biomolecules 2021, 11(9), 1320; https://doi.org/10.3390/biom11091320 - 6 Sep 2021

Cited by 55 | Viewed by 25330

Abstract

Naegleria fowleri is a free-living amoeba (FLA) that is commonly known as the “brain-eating amoeba.” This parasite can invade the central nervous system (CNS), causing an acute and fulminating infection known as primary amoebic meningoencephalitis (PAM). Even though PAM is characterized by low [...] Read more.

Naegleria fowleri is a free-living amoeba (FLA) that is commonly known as the “brain-eating amoeba.” This parasite can invade the central nervous system (CNS), causing an acute and fulminating infection known as primary amoebic meningoencephalitis (PAM). Even though PAM is characterized by low morbidity, it has shown a mortality rate of 98%, usually causing death in less than two weeks after the initial exposure. This review summarizes the most recent information about N. fowleri, its pathogenic molecular mechanisms, and the neuropathological processes implicated. Additionally, this review includes the main therapeutic strategies described in case reports and preclinical studies, including the possible use of immunomodulatory agents to decrease neurological damage. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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