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Evaluating precision medicine approaches for gene therapy in patient-specific cellular models of Bietti crystalline dystrophy.
Li, Yao; Yang, Richard R; Li, Yong-Shi; Hsu, Chun-Wei; Jenny, Laura A; Kong, Yang; Ruan, Merry Zc; Sparrow, Janet R; Tsang, Stephen H.
Afiliación
  • Li Y; Jonas Children's Vision Care, Department of Ophthalmology, Columbia University, New York, New York, USA.
  • Yang RR; Reflection Biotechnologies, New Territories, Hong Kong.
  • Li YS; Jonas Children's Vision Care, Department of Ophthalmology, Columbia University, New York, New York, USA.
  • Hsu CW; Jonas Children's Vision Care, Department of Ophthalmology, Columbia University, New York, New York, USA.
  • Jenny LA; Jonas Children's Vision Care, Department of Ophthalmology, Columbia University, New York, New York, USA.
  • Kong Y; Jonas Children's Vision Care, Department of Ophthalmology, Columbia University, New York, New York, USA.
  • Ruan MZ; Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
  • Sparrow JR; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA.
  • Tsang SH; Jonas Children's Vision Care, Department of Ophthalmology, Columbia University, New York, New York, USA.
JCI Insight ; 9(16)2024 08 22.
Article en En | MEDLINE | ID: mdl-39171529
ABSTRACT
Patient-specific induced pluripotent stem cell-derived (iPSC-derived) cell lines allow for therapies to be tailored to individual patients, increasing therapeutic precision and efficiency. Bietti crystalline dystrophy (BCD) is a rare blinding disease estimated to affect about 67,000 individuals worldwide. Here, we used iPSC-derived retinal pigment epithelium (iRPE) cells from patients with BCD to evaluate adeno-associated virus-mediated (AAV-mediated) gene augmentation therapy strategies. We found that BCD iRPE cells were vulnerable to blue light-induced oxidative stress and that cellular phenotype can be quantified using 3 robust biomarkers reactive oxygen species (ROS), 4-hydroxy 2-nonenal (4-HNE) levels, and cell death rate. Additionally, we demonstrated that AAV-mediated gene therapy can significantly reduce light-induced cell death in BCD iRPE cells. This is the first proof-of-concept study to our knowledge to show that AAV-CYP4V2 gene therapy can be used to treat light-induced RPE damage in BCD. Furthermore, we observed significant variability in cellular phenotypes among iRPE from patients with BCD of divergent mutations, which outlined genotype-phenotype correlations in BCD patient-specific cell disease models. Our results reveal that patient-specific iRPE cells retained personalized responses to AAV-mediated gene therapy. Therefore, this approach can advance BCD therapy and set a precedent for precision medicine in other diseases, emphasizing the necessity for personalization in healthcare to accommodate individual diversity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Distrofias Hereditarias de la Córnea / Dependovirus / Epitelio Pigmentado de la Retina / Células Madre Pluripotentes Inducidas / Medicina de Precisión Límite: Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Distrofias Hereditarias de la Córnea / Dependovirus / Epitelio Pigmentado de la Retina / Células Madre Pluripotentes Inducidas / Medicina de Precisión Límite: Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos