Can Enzyme Replacement Therapy revert iNKT cell dysfunction in Acid Sphingomyelinase Deficiency patients?

Investigador: Fátima Macedo
PhD in Biomedical Sciences, Senior Researcher, Instituto de Investigação e Inovação em Saúde (i3S) in Porto University

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of the enzyme acid sphingomyelinase (ASM), resulting in an abnormal accumulation of sphingomyelin in lysosomes. The abnormal accumulation of sphingomyelin, a crucial cell membrane component, ultimately impairs pulmonary, hepatic, and neurological functions, with severe forms of the disease being fatal in the first years of life.

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Improve management of MADD patients: a curated database with clinical, molecular and cellular information

Investigador: Bárbara J. Henriques
Ph.D., APhD Senior Researcher, BioISI – Biosystems & Integrative Science Institute Faculty of Sciences, University of Lisbon

Inborn errors of metabolism comprise a class of genetic diseases which affect genes coding for enzymes involved in different cellular pathways. The expansion of the newborn screening program allows the earlier identification of several new cases associated to these rare diseases. Still clinicians and researchers in the field identified an enormous gap, the lack of a unifying depository for molecular and clinical data on patients, with the majority of cases found disperse in literature, and many not even reported in international journal with full access to all.

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Novel insights into treatment strategies for hyperammonemia-associated urea cycle disorders and organic acidurias.

Investigador: Margarida F.B. e Silva
Ph.D., Aux Prof FFUL; Metabolism and Genetics Group at iMed.UL

Hyperammonemia in paediatric patients is mostly related to inborn errors of metabolism (IEM) including urea cycle disorders and certain organic acidurias. The rise of toxic ammonia levels may have devastating consequences on neurodegeneration and neurodevelopment. Preventive strategies of metabolic deterioration and more effective therapeutic options are definitely needed. Few studies have assessed the efficacy of novel therapies, especially tailored to the various phenotypes and IEM. This research proposal puts forward the hypotheses that: 1) hyperammonemia is linked to changes in cofactors or redox status affecting energy metabolism and resulting in mitochondrial dysfunction; 2) drug design profits of associated small molecules to improve their efficacy, reducing levels of toxic ammonia and surpassing the metabolic imbalances associated with the genetic underlying cause of IMD.

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Something stinks’: impaired hydrogen sulfide and cysteine persulfide production by cystathionine β-synthase variants identified in classical homocystinuria patients

Investigador: João B. Vicente
Auxiliary Investigator, ITQB-NOVA

This project aims to shed new lights onto the molecular basis of classical homocystinuria (CHU) due to cystathionine-β-synthase (CBS) deficiency, resulting from CBS gene mutations. The CBS canonical role in the transsulfuration branch of methionine metabolism has been increasingly extended to a major role as an endogenous source of hydrogen sulfide (H2S) source and, secondarily, cysteine persulfide (CysSSH). H2S regulates many physiological processes as a multifaceted ubiquitous signaling molecule. Disturbed H2S metabolism due to aberrant CBS expression is growingly established as an etiologic factor of several pathologies, some with clinical presentations common to CHU, namely cardiovascular disease and neurological impairment. Given that elevated plasma homocysteine does not fully explain the clinical presentations of CHU patients, impaired H2S and/or CysSSH production are likely to underlie the pathogenicity of various CBS mutations.
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Skipping the Pathology in Rare Diseases: Antisense exon-skipping therapy for Mucolipidosis type II

Investigador: Sandra Alves: Research and Development Unit, Department of Human Genetics. National Health Institute Doutor Ricardo Jorge.

Studies will be carried out by the Lysosomal Storage Disease (LSD) research group from Department of Genetics of the National Institute of Health Dr. Ricardo Jorge (INSA-Porto) where all the facilities for the proposed studies are available and well-established. The LSD group has been conducting studies on the mutational spectrum of several rare diseases (namely LSDs) in Portugal addressing also the impact of identified mutations on RNA and protein levels. The development of alternative therapeutic approaches is also a major research focus and recently antisense oligonucleotides-based therapeutic approaches to correct pathogenic effects of some LSDs mutations.

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Genetic Substrate Reduction Therapy for Mucopolysaccharidoses Toward a siRNA-containing nanoparticle targeted to brain cells

Investigador: Francisca Coutinho Instituição: Unidade de I&D, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge

Impaired degradation of glycosaminoglycans (GAGs) with consequent intralysosomal accumulation of undegraded products causes a group of lysosomal storage disorders known as mucopolysaccharidoses (MPSs). As it happens for most LSDs, there is no fully effective treatment for MPSs. In fact, even though enzyme replacement therapy does exist for 4 MPSs, this approach is ineffective for the brain since recombinant enzymes are not able to cross the blood brain barrier. This is one of the reasons why other therapies need to be tested for MPSs with central nervous system involvement. Having this in mind, we have designed an RNA-based strategy based upon the selective downregulation of two genes involved in the biosynthesis of GAGs. Our goal is to promote an effective reduction of the accumulating substrate, ultimately decreasing or delaying MPSs’ symptoms. As tools to achieve substrate reduction, we are currently evaluating a specific type of antisense oligonucleotides, which are able to trigger a naturally-occurring post-transcriptional gene silencing process called RNA interference: the small interfering RNAs (siRNAs). So far, the obtained results are quite promising, with marked decreases of the target mRNA levels, which resulted in significant reductions in GAGs’ storage.

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CYP46A1 AS A NEW THERAPEUTIC TARGET IN NIEMANN-PICK TYPE C DISEASE

Investigador: Elsa Rodrigues
Instituição: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de
Lisboa (FF/ULisboa), Lisbon, Portugal

Due to its importance in neuronal function, we have been devoted to the characterization of the molecular pathways involved in the control of brain cholesterol metabolism, focusing on the role of CYP46A1. The neuronal specific cholesterol 24-hydroxylase, encoded by the cytochrome P450 CYP46A1 gene, is responsible for the conversion of cholesterol into 24S-hydroxycholesterol, which accounts for the major elimination pathway of brain cholesterol. Due to its importance in cholesterol elimination we hypothesized that CYP46A1 could be a new therapeutic target in Niemann-Pick type C disease (NPC1 - Rare Disease ORPHA646). NPC disease is a lysosomal
storage disorder, characterized by cholesterol accumulation in the late endosomes/ lysosomes compartment, which results from mutations in NPC1 or NPC2 genes. The most dominant feature is the progressive neurodegeneration leading to premature childhood death.

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Investigador: Isabel Antolin Rivera
Instituição:Grupo Metabolismos e Genética - Research Institute for Medicines (iMed.ILisboa), Faculdade de Farmácia da Universidade de Lisboa

Pyruvate is a key molecule in human metabolism once it links glycolysis to energy production via Krebs cycle and respiratory chain. Nevertheless, the pyruvate oxidation route is an intricate metabolic pathway as it encompasses all the steps mediating the passage of pyruvate from cytoplasm to mitochondrial matrix until its conversion to acetyl-CoA and, additionally, every step is regulated by specific proteins. Accordingly, an insufficient pyruvate turnover in mitochondria ussually originates severe clinical phenotypes.

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Investigador: Paula Peralta
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa

The current universal established PKU treatment relies on a highly restrictive diet of difficult compliance which may compromise the patient’s neurologic outcome and decrease their quality of life. The use of the pharmacological form of the natural hPAH cofactor BH4 has been recently approved by American and European authorities and a pegylated (PEG) form of a recombinant non-mammalian L-Phe degrading enzyme (phenylalanine ammonia lyase; PAL) already reached Phase III clinical trials. However, BH4 supplementation only allow diet liberalization in the restrict group of PKU patients presenting the mild form and PEG-PAL administration has been reported as potentially immunogenic. Therefore, a safety and efficacious treatment for all forms of PKU is still needed.

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Investigador: Manuela Grazina
Instituição: Center for Neuroscience and Cell Biology – CNC, University of Coimbra

LHON is a maternally inherited optic atrophy with acute bilateral loss of central vision, mainly associated to specific mtDNA mutations, affecting MRC-complex I subunits. This study aims to provide new insights on mitochondria networks and alternatives routes for proteins transport into mitochondria.

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Adapting protein homeostasis in inborn errors of metabolism: treatment of severe forms of phenylketonuria 

Investigador: João Leandro
Instituição: Met&Gen, Faculdade de Farmácia de Lisboa

The aim of this study is to modulate the cytosolic proteostasis network to treat severe forms of phenylketonuria, caused by misfolding of phenylalanine hydroxylase.

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Investigador: Lígia S. Almeida
Instituição: Departamento de Genética – INSA, Porto

Este estudo tem como objetivo a implementação de uma nova estratégia para a sequenciação completa do mtDNA usando as novas tecnologias de sequenciação massiva e definição de um algoritmo de análise.

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Investigador: Isabel Antolin Rivera
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa

Os principais objectivos deste estudo são a elucidação dos mecanismos patogénicos subjacentes às mutações de splicing detectadas em doentes galactosémicos da população Portuguesa, bem como o estudo do efeito de sondas oligonucleotídicas anti-sense na recuperação da anomalia introduzida pelas mutações de splicing.

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Investigador: Hugo Daniel Carvalho de Azevedo Rocha
Instituição: Departamento de Genética – INSA, Porto

O objectivo global deste projecto é definir as consequências dos défices múltiplos das desidrogenases (défices de ETF e ETF:QO) no proteoma mitocondrial, gerando novos dados que permitam compreender a patofisiologia associada a esta doença metabólica.

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Investigador: Maria de Fátima Vieira Ventura
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa

Neste projecto pretende-se avaliar funcional e estruturalmente as duas novas variantes de MCAD. Pretende-se igualmente proceder à caracterização de proteínas híbridas de modo a avaliar a ocorrência de uma eventual complementação interalélica.

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