NOTCH3 Variant Affects Bone Formation and Can Be Targeted with Antisense Oligonucleotides
Author Information
Author(s): Canalis Ernesto, Yu Jungeun, Schilling Lauren, Jafar-nejad Paymaan, Carrer Michele
Primary Institution: UConn Musculoskeletal Institute, UConn Health, Farmington, CT, United States of America
Hypothesis
A NOTCH3 pathogenic variant influences osteogenesis and can be targeted by antisense oligonucleotides in induced pluripotent stem cells.
Conclusion
The NOTCH3 pathogenic variant leads to a modest increase in bone cell formation in human stem cells, and specific antisense oligonucleotides can effectively reduce the expression of both normal and mutant NOTCH3.
Supporting Evidence
- A NOTCH3 pathogenic variant causes a modest increase in osteoblastogenesis in human iPS cells in vitro.
- NOTCH3 and NOTCH3 mutant specific ASOs downregulate NOTCH3 transcripts associated with Lateral Meningocele Syndrome.
- ASOs targeting NOTCH3 decreased both NOTCH3 wild type and NOTCH36692-93insC mutant mRNA significantly.
Takeaway
Scientists found that a specific gene change can make bone cells grow a little more in the lab, and they can use special medicines to help control this change.
Methodology
Induced pluripotent stem cells were created with a NOTCH3 mutation and differentiated into bone-forming cells, with the effects of antisense oligonucleotides tested on gene expression.
Potential Biases
Potential bias due to funding from Ionis Pharmaceuticals, which provided the antisense oligonucleotides used in the study.
Limitations
The study was conducted in vitro, and the effects on bone formation in living organisms were not assessed.
Participant Demographics
iPS cells were derived from male CD14+ cord blood.
Statistical Information
P-Value
p<0.05
Statistical Significance
p<0.05
Digital Object Identifier (DOI)
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