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H. Kaneko, M. E. Kleinman, W. Cho, J. Z. Baffi, K. Saito, M. G. Rich, R. J. C. Albuquerque, J. Ambati; TLR3 Inhibitors Blocks Double Stranded RNA-Induced Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3519.
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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.
Poly I:C12U (AmpligenTM), 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.
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
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.
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