TLR3 Inhibitors Blocks Double Stranded RNA-Induced Retinal Degeneration

Abstract

Purpose: : We recently showed that 21-nt nucleotide (nt) or longer small interfering RNAs (siRNAs) activate double stranded RNA (dsRNA) sensor toll-like receptor-3 (TLR3) in a sequence-independent manner (Kleinman et al. Nature 2008) and that TLR3 activation by poly I:C, a synthetic long dsRNA, induces retinal degeneration in mice (Yang et al. NEJM 2008). We studied the effect of a novel class of TLR3 inhibitors (TLR3i) on dsRNA-induced retinal degeneration in vivo.

Methods: : Poly I:C₁₂U (Ampligen^TM), a more selective ligand of TLR3 than poly I:C, was intravitreously injected into wild-type or Tlr3^-/- mice. TUNEL staining, caspase-3 activation, EM, and ERG were used to assess functional rescue of Ampligen by co-administration of TLR3i.

Results: : Ampligen induced retinal degeneration in wild-type but not Tlr3^-/- mice. TLR3i prevented Ampligen-induced retinal degeneration in wild-type mice, as monitored by fundus examination, EM and ERG. It also blocked Ampligen-induced retinal apoptosis as monitored by TUNEL and caspase-3 activation

Conclusions: : These findings, in concert with earlier observations, reveal a potential pathogenetic role for long dsRNA in the development of human AMD and suggest the viability of TLR3 inhibition as a novel therapeutic strategy.

Keywords: age-related macular degeneration • retinal degenerations: cell biology • drug toxicity/drug effects