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Targeted degradation of VEGF with bispecific aptamer-based LYTACs ameliorates pathological retinal angiogenesis.
Zhou, Ping; Zhang, Sai; Li, Lin; Zhang, Renshuai; Guo, Guizhi; Zhang, Yufei; Wang, Runa; Liu, Miaoyuan; Wang, Zhiyi; Zhao, Huijie; Yang, Guiwen; Xie, Songbo; Ran, Jie.
Afiliación
  • Zhou P; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Zhang S; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Li L; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Zhang R; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Guo G; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Zhang Y; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Wang R; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Liu M; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Wang Z; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Zhao H; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Yang G; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Xie S; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
  • Ran J; Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
Theranostics ; 14(13): 4983-5000, 2024.
Article en En | MEDLINE | ID: mdl-39267779
ABSTRACT
Rationale Neovascular ocular diseases (NODs) represent the leading cause of visual impairment globally. Despite significant advances in anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF), persistent challenges remain prevalent. As a proof-of-concept study, we herein demonstrate the effectiveness of targeted degradation of VEGF with bispecific aptamer-based lysosome-targeting chimeras (referred to as VED-LYTACs).

Methods:

VED-LYTACs were constructed with three distinct modules a mannose-6-phosphate receptor (M6PR)-binding motif containing an M6PR aptamer, a VEGF-binding module with an aptamer targeting VEGF, and a linker essential for bridging and stabilizing the two-aptamer structure. The degradation efficiency of VED-LYTACs via the autophagy-lysosome system was examined using an enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. Subsequently, the anti-angiogenic effects of VED-LYTACs were evaluated using in vitro wound healing assay, tube formation assay, three-dimensional sprouting assay, and ex vivo aortic ring sprouting assay. Finally, the potential therapeutic effects of VED-LYTACs on pathological retinal neovascularization and vascular leakage were tested by employing mouse models of NODs.

Results:

The engineered VED-LYTACs promote the interaction between M6PR and VEGF, consequently facilitating the translocation and degradation of VEGF through the lysosome. Our data show that treatment with VED-LYTACs significantly suppresses VEGF-induced angiogenic activities both in vitro and ex vivo. In addition, intravitreal injection of VED-LYTACs remarkably ameliorates abnormal vascular proliferation and leakage in mouse models of NODs.

Conclusion:

Our findings present a novel strategy for targeting VEGF degradation with an aptamer-based LYTAC system, effectively ameliorating pathological retinal angiogenesis. These results suggest that VED-LYTACs have potential as therapeutic agents for managing NODs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neovascularización Retiniana / Factor A de Crecimiento Endotelial Vascular / Aptámeros de Nucleótidos / Lisosomas Límite: Animals / Humans Idioma: En Revista: Theranostics Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neovascularización Retiniana / Factor A de Crecimiento Endotelial Vascular / Aptámeros de Nucleótidos / Lisosomas Límite: Animals / Humans Idioma: En Revista: Theranostics Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia