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<p>The U1 small nuclear ribonucleoprotein (snRNP) complex is essential for pre-mRNA splicing and inhibition of premature polyadenylation. Its dysfunction has been implicated in various cancers, including glioblastoma, driving oncogenic splicing and tumor progression. This study explored the potential of APT20TTMG, a synthetic cDNA that modulates U1 snRNP misassembly, in glioblastoma. The internalization of APT20TTMG was assessed in U-87 MG cells, as well as its effects on cell viability, proliferation, and apoptosis. Athymic mice were used to evaluate the effects of intravenous APT20TTMG administration on tumor-related parameters. APT20TTMG exhibited over 50% internalization, exerting cytotoxic, cytostatic, and pro-apoptotic effects in vitro. A 22-day treatment with APT20TTMG reduced tumor volume, slowed tumor growth, and showed a trend toward increased body weight. Treatment also decreased oncogenic pathways and tended to enhance histopathological outcomes. A pilot study combining APT20TTMG with temozolomide further improved antitumor efficacy. Our results demonstrate that APT20TTMG has strong potential in correcting U1 snRNP complex dysfunction, supporting its further investigation as a strategy to modulate splicing in glioblastoma.</p>

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Effects of APT20TTMG, a modulator of the U1 snRNP complex, in glioblastoma models

  • 期刊论文

  • 发表日期：

    2025年10月2日

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  • Caio Bruno Quinta de Souza Leal,
  • Camila Guimarães Moreira Zimmer,
  • Vanessa de Vasconcelos Castilho Sinatti,
  • Ericks Sousa Soares,
  • Michael S. Rafii,
  • Rafael Mantovani Bottos

摘要

The U1 small nuclear ribonucleoprotein (snRNP) complex is essential for pre-mRNA splicing and inhibition of premature polyadenylation. Its dysfunction has been implicated in various cancers, including glioblastoma, driving oncogenic splicing and tumor progression. This study explored the potential of APT20TTMG, a synthetic cDNA that modulates U1 snRNP misassembly, in glioblastoma. The internalization of APT20TTMG was assessed in U-87 MG cells, as well as its effects on cell viability, proliferation, and apoptosis. Athymic mice were used to evaluate the effects of intravenous APT20TTMG administration on tumor-related parameters. APT20TTMG exhibited over 50% internalization, exerting cytotoxic, cytostatic, and pro-apoptotic effects in vitro. A 22-day treatment with APT20TTMG reduced tumor volume, slowed tumor growth, and showed a trend toward increased body weight. Treatment also decreased oncogenic pathways and tended to enhance histopathological outcomes. A pilot study combining APT20TTMG with temozolomide further improved antitumor efficacy. Our results demonstrate that APT20TTMG has strong potential in correcting U1 snRNP complex dysfunction, supporting its further investigation as a strategy to modulate splicing in glioblastoma.