Percorrer por autor "Pires, Joana Gonçalo"
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- Evaluation of the therapeutic effect of human IPSC-derived neuroephitelial stem cells in an immunocompromised lentiviral-induced Machado Joseph Disease mouse modelPublication . Pires, Joana Gonçalo; Mendonça, Liliana Simões; Nóbrega, Clévio; Almeida, Luís Pereira deMachado-Joseph Disease (MJD), or Spinocerebellar Ataxia Type 3 (SCA3), is a dominantly inherited neurodegenerative disorder caused by CAG repeat expansion in the ATXN3 gene, resulting in a polyglutamine-expanded ataxin-3 protein that forms toxic intranuclear aggregates. With no current disease-modifying therapies, novel approaches targeting the molecular and cellular basis of MJD are urgently needed. This study evaluated the therapeutic potential of neuroepithelial stem cells (Nesc) derived from human induced pluripotent stem cells (iPSCs), both CNT (not bearing the mutant ataxin-3) (CNT NESC) and MJD cells genetically engineered with allele-specific shRNAs targeting mutant ATXN3 RNA (Silenced MJD NESC), following striatal transplantation in NOD/SCID mice injected with lentivirus encoding for mutant ataxin-3 ( lentiviral-induced MJD mouse model). Our results demonstrate that both CNT and silenced MJD NESC are prone to survive up to eight weeks after transplantation into the striatum of NOD/SCID mice also injected with lentivirus encoding for mutant ataxin-3. Both cell types triggered a tendency reduction in the size of the inclusions. Western blot analysis showed a modest, non-significant decrease in high-molecular-weight ATXN3 aggregates in the silenced MJD NESC group. Additionally, no significant differences were observed between CNT mice and CNT and Silenced MJD NESC groups regarding microglia recruitment. RT-qPCR analysis revealed that the striatum of mice transplanted with CNT NESC and Silenced MJD NESC expressed higher Notch1 mRNA levels, and tendency increased for both Bdnf and Ngf mRNA levels. These results demonstrated the ability of NESC to trigger the bystander effects and enhance neurogenesis-related and neurotrophic factors levels after transplantation in the lentiviral-induced MJD mouse model. Collectively, these findings support the therapeutic promise of combining targeted gene silencing of MJD patients’ iPSC-derived NESC with NESC transplantation in MJD mouse models.