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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.



The success achieved at cellular level is now the trigger for the current application and, even though we are evaluating cell lines from all different MPS after transfection with the designed siRNAs and work is still ongoing, that will not be the focus of this application. Knowing that the translation of siRNAs from the bench to the clinic may be hindered by their limited cellular uptake, low biological stability and unfavorable pharmacokinetics, the development of an appropriate delivery method is mandatory if we want to proceed with these preclinical studies. Therefore, the main aim of this project is to address delivery of the siRNAs under evaluation to allow stable complexation and protection of nucleic acids, so that they may work not only in cell culture but also in animal models and, hopefully, patients. To do so, we have established collaboration with one of the pioneer Portuguese teams who demonstrated the feasibility of systemic administration of either chemically modified or complexed siRNAs, at the Centro de Neurociências e Biologia Celular (CNBC/UC). With their support, we will test an innovative and versatile non-viral system to promote brain delivery of the selected siRNAs with different lipid nanocarriers: targeted stable nucleic acid lipid particles (t-SNALPs) coupled with two different ligands able to promote cell uptake of lipid-based nanosystems in a large variety of cells, including neurons.
This is, therefore, the sole goal of this application: to develop and evaluate a solution to allow targeted delivery of our substrate reduction therapy approach for MPSs.

Consulte Grelha de Avaliação



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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