Calcium-Enhanced Medium-Based Delivery of Splice Modulating Antisense Oligonucleotides in 2D and 3D hiPSC-Derived Neuronal Models

Calcium-Enhanced Medium-Based Delivery of Splice Modulating Antisense Oligonucleotides in 2D and 3D hiPSC-Derived Neuronal Models

Antisense technology demonstrates significant potential for addressing inherited brain diseases, with over a dozen products already available and numerous others in the development pipeline. The versatility of differentiating induced pluripotent stem cells (iPSCs) into nearly all neural cell types p...

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Bibliographic Details
Published in:Biomedicines Vol. 12; no. 9; p. 1933
Main Authors: Buijsen, Ronald A M, van der Graaf, Linda M, Kuijper, Elsa C, Pepers, Barry A, Daoutsali, Elena, Weel, Lotte, Raz, Vered, Parfitt, David A, van Roon-Mom, Willeke M C
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01-09-2024
MDPI
Subjects:
Antisense oligonucleotides
Antisense therapy
ASO delivery
Astrocytes
Brain
Cell culture
Cell differentiation
CEM
Diagnostic reagents industry
Disease
Drug development
Efficiency
Electroporation
Inhibitory postsynaptic potentials
Nervous system diseases
Neural stem cells
Neurodevelopmental disorders
Neurological diseases
Neurological disorders
Neurons
Neurotoxicity
Nucleic acids
Organoids
Phenotypes
Pluripotency
Toxicity
Transfection
Canada
organoids
ASO delivery
CEM
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Summary:Antisense technology demonstrates significant potential for addressing inherited brain diseases, with over a dozen products already available and numerous others in the development pipeline. The versatility of differentiating induced pluripotent stem cells (iPSCs) into nearly all neural cell types proves invaluable for comprehending the mechanisms behind neurological diseases, replicating cellular phenotypes, and advancing the testing and development of new therapies, including antisense oligonucleotide therapeutics. While delivering antisense oligonucleotides (ASOs) to human iPSC-based neuronal models has posed challenges, this study explores various delivery methods, including lipid-based transfection, gymnotic uptake, Ca -enhanced medium (CEM)-based delivery, and electroporation, in 2D and 3D hiPSC-derived neuronal models. This study reveals that CEM-based delivery exhibits efficiency and low toxicity in both 2D neuronal cultures and 3D brain organoids. Furthermore, the findings indicate that CEM is slightly more effective in neurons than in astrocytes, suggesting promising avenues for further exploration and optimization of preclinical ASO strategies in the treatment of neurological disorders.
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ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines12091933