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Projeto de investigação
Development of a Genetic Substrate Reduction Therapy for MPS III using Antisense Oligonucleotides as therapeutic agents
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Autores
Publicações
mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesis
Publication . Santos, Juliana I.; Gonçalves, Mariana; Almeida, Matilde B.; Rocha, Hugo; Duarte, Ana J.; Matos, Liliana; Moreira, Luciana V.; Encarnação, Marisa; Gaspar, Paulo; Prata, Maria J.; Coutinho, Maria F.; Alves, Sandra
Mucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.
Gapmer Antisense Oligonucleotides as a New Class of Genetic Substrate Reduction Agents in Mucopolysaccharidosis IIIC
Publication . Santos, Juliana I.; Gonçalves, Mariana; Almeida, Matilde B.; Rocha, Hugo; Duarte, Ana J.; Matos, Liliana; Moreira, Luciana V.; Encarnação, Marisa; Gaspar, Paulo; Prata, Maria J.; Coutinho, Maria F.; Alves, Sandra
Background: Lysosomal storage disorders (LSDs) include over 70 rare inherited metabolic diseases caused by defective lysosomal enzymes or associated proteins, leading to the accumulation of undegraded substrates and progressive cellular dysfunction. Among these, Mucopolysaccharidoses (MPS) are a group characterized by storage of undegraded glycosaminoglycans (GAGs), including heparan, dermatan, keratan, and chondroitin sulfates. MPS type III (as known as Sanfilippo syndrome) predominantly affects the central nervous system (CNS) and manifests as severe neurodegeneration, behavioral abnormalities and cognitive decline. The subtype IIIC results from deficient activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT) enzyme. Currently, treatment options for MPS III are limited, increasing the need to find alternative therapies. RNA-based therapies have recently gained attention as powerful alternatives to traditional treatments, with several already approved for clinical use in other diseases. Among these, antisense oligonucleotides (ASOs) stand out as a highly promising class of molecules for personalized medicine. ASOs are short, chemically synthesized strands of nucleic acids designed to bind specifically to target RNA sequences, thereby influencing gene expression.
In this work, we explored the application of gapmer ASOs as a genetic substrate reduction therapy (gSRT) for MPS IIIC, with the goal of decreasing the expression of a gene, XYLT1, involved in the synthesis of the accumulated substrate, heparan sulfate (HS).
Unidades organizacionais
Descrição
Palavras-chave
RNA therapeutics,Rare Diseases,Antisense Oligonucleotides,Pre-clinical validation, Medical and health sciences
Contribuidores
Financiadores
Entidade financiadora
Fundação para a Ciência e a Tecnologia, I.P.
Fundação para a Ciência e a Tecnologia, I.P.
Fundação para a Ciência e a Tecnologia, I.P.
Programa de financiamento
Concurso de Projetos de I&D em Todos os Domínios Científicos - 2022 - PEX
Concurso de Projetos de I&D em Todos os Domínios Científicos - 2022
Concurso de Projetos de I&D em Todos os Domínios Científicos - 2022
Número da atribuição
2022.04667.PTDC