Modulation of TTR gene expression in the eye using modified siRNAs

Area of Science:

• Ophthalmology
• Molecular Biology
• Drug Delivery

Background:

• Small interfering RNAs (siRNAs) are established therapeutics for liver gene silencing.
• Transthyretin (TTR) amyloidosis affects the eye, necessitating ocular TTR gene expression reduction.
• Current systemic siRNA therapies target liver TTR expression, but ocular delivery remains a challenge.

Purpose of the Study:

• To investigate the efficacy of lipid-modified siRNAs for inhibiting TTR gene expression in the eye.
• To evaluate intravitreal injection as a local delivery method for ocular siRNA therapy.
• To explore the potential of siRNA-based therapies for treating ocular TTR amyloidosis.

Main Methods:

• Development and formulation of pyrimidine C5- and 2'-O-linked lipid-modified siRNAs in saline.
• Administration of lipid-modified siRNAs via intravitreal injection in an ocular model.
• Assessment of TTR gene expression inhibition in ocular tissues.
• Comparison of lipid-modified siRNAs with GalNAc-modified siRNAs for ocular delivery.

Main Results:

• Pyrimidine C5- and 2'-O-linked lipid-modified siRNAs successfully inhibited TTR gene expression in the eye following intravitreal administration.
• Lipid chain length and accessibility were identified as factors influencing in vivo silencing efficacy.
• GalNAc-modified siRNAs also demonstrated TTR inhibition, though with lower potency compared to lipid-modified versions.
• Demonstrated widespread inhibition of TTR expression throughout ocular tissues.

Conclusions:

• Lipid-modified siRNAs delivered via intravitreal injection are effective for inhibiting ocular TTR gene expression.
• This approach holds significant potential for treating the ocular complications associated with TTR amyloidosis.
• Lipid-siRNA conjugates represent a versatile platform for developing novel ocular drug delivery strategies.