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2018

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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2017

 

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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2016

  Next-generation sequencing for the molecular characterization of pyruvate dehydrogenase complex deficiency due to primary secondary causes

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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2015

New approaches for the treatment of Phenylketonuria: Evaluation of human phenylalanine hydroxylase (hPAH) formulations in cellular models  

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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2014

Unveiling Intracellular Organelle Interaction with mitochondria in Leber hereditary optic neuropathy: Functional genomics approach

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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2012

Novel Approach for the Analysis of Whole Mitochondrial DNA by Massive Parallel Sequencing 

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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2011

Galactosémia clássica: Caracterização funcional de mutações de splicing e sua modulação por sondas anti-sense 

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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2010

Disfunção mitocondrial nos défices múltiplos das desidrogenases 

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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Deficiência na desidrogenase dos ésteres acil-coenzima A de cadeia média (MCAD):
Caracterização funcional e estrutural de proteínas mutantes
 

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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CONTACTOS

Faculdade de Farmácia da U.L.
Av. Prof. Gama Pinto
1649-003 Lisboa
Portugal

Contacto: Fernanda Asper
Telefone.: +351 217 946 400
Fax: +351 217 946 491
spdm@ff.ul.pt


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