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Development of a U1 snRNA-adapted gene therapeutic strategy to correct 5’ splicing defects in lysosomal storage disorders.

Investigador: Liliana Matos
Instituição: Departamento de Genética Humana – INSA, Porto



Splicing defects are among the most frequent pathogenic mechanisms underlying genetic diseases. Thus, correction of erroneous splicing is an important goal for which novel pharmacological and “molecular” therapies have begun to be designed and tested.

Lysosomal storage disorders (LSDs) are a group of inherited diseases that can result in severe and progressive pathology due to a specific lysosomal dysfunction. Mucopolysaccharidosis 1 (Hurler; Hurler-Scheie; Scheie syndromes) is a LSD caused by mutations in the IDUA gene, encoding an enzyme involved in heparan and dermatan sulphate degradation in lysosomes. Another group of LSDs comprises the Mucolipidosis II (l-cell) and III (pseudo Hurler polydystrophy) which are autosomal recessive disorders due to mutations in the GNPTAB and GNPTG genes encoding the a/β and y-subunits of the GIcNAc-1-phosphotransferase, respectively. This protein has a subunit structure of α2β2y2 and initiates the first step of tagging lysosomal enzymes with mannose-6-phosphate. Splicing mutations are frequent in MPS 1 (~16%) and ML’s (~11%). From these, 67% in MPS 1 and 47% in ML’s corresponds to 5’ donor site mutations which thus constitute a good target for mutation specific therapeutic approaches.

Although the existence of therapeutic treatment options for MPS 1, they have some limitations and for ML’s there is no therapeutic treatment available. Therefore, for splicing mutations, splicing therapeutics is a potential alternative or an adjunct therapeutic strategy for these diseases. Here, an antisense-snRNA therapeutic strategy will be developed for the IDUA (c.1650+5G>A) and GNPTAB (c.3335+6T>G) mutations present respectively in a MPS 1 and ML III patient’s. To restore the correct mRNA splicing pattern, mutation-adapted U1snRNA vectors will be used in a model celI line with mutation-disease minigenes as well as directly in patient’s fibroblasts through the implementation of the transduction lentiviral technique.



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

Contacto: Fernanda Asper
Telefone.: +351 217 946 400
(Chamada para a rede fixa nacional)
Fax: +351 217 946 491


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