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Modulation of TTR Gene Expression in the Eye using Modified Duplex RNAs
Jiaxin Hu1, Xin Gong2, Jayanta Kundu3
1UT Southwestern Medical Center, Departments of Pharmacology and Biochemistry, Dallas TX 75390, USA.
Biorxiv : the Preprint Server for Biology
|March 31, 2025
Summary
Lipid-modified short interfering RNAs (siRNAs) effectively inhibit transthyretin (TTR) gene expression in the eye via intravitreal injection. This approach offers a promising strategy for treating ocular TTR amyloidosis.
Area of Science:
- Ophthalmology
- Molecular Biology
- Drug Delivery
Background:
- Small interfering RNAs (siRNAs) are established for liver gene silencing.
- Transthyretin (TTR) amyloidosis affects the eye, necessitating ocular gene expression control.
- Systemic anti-TTR siRNAs treat liver TTR expression but not ocular manifestations.
Purpose of the Study:
- To investigate the efficacy of lipid-modified siRNAs for inhibiting ocular TTR gene expression.
- To evaluate intravitreal injection as a delivery method for ocular RNA interference (RNAi).
Main Methods:
- Local intravitreal (IVT) injection of C5 and 2'-O-linked lipid-modified siRNAs in saline.
- Assessment of TTR gene expression inhibition in ocular tissues.
- Comparison with GalNAc-modified anti-dsRNAs.
Main Results:
- Lipid-modified siRNAs successfully inhibited TTR gene expression in the eye following IVT administration.
- Lipid chain length and accessibility correlated with in vivo silencing efficacy.
- GalNAc-modified siRNAs showed TTR inhibition, but with lower potency.
Conclusions:
- Lipid-modified siRNAs delivered via IVT injection are effective for inhibiting ocular TTR expression.
- This strategy holds potential for treating ocular TTR amyloidosis.
- Lipid-siRNA conjugates represent a versatile platform for ocular drug discovery.
Keywords:
RNAiTTR amyloidosiscorneaduplex RNAintraocularintravitrealretinaretinal pigment epitheliumtransthyretinMore Related Videos
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