Amelioration of Photoreceptor Degeneration in a Mouse Model of P23H ADRP Using an Antisense Oligonucleotide (ASO)

Abstract

 

Purpose

 

Antisense technology provides an ideal platform for the treatment of autosomal dominant genetic diseases in the eye. We explored the pharmacological benefits of ASO mediated reduction of human P23H transgene mRNA in a mouse model of P23H ADRP.

 

Methods

 

Transgenic (Tg) mice harboring human rhodopsin genomic sequence with the P23H variant were used to evaluate efficacy (mRNA knockdown) and pharmacology (ONL thickness) of ASOs by IVT delivery. Tg mice were dosed intravitreally with 1 uL of either PBS, 50 ug of P23H ASO or control ASO and sacrificed 7-60 d later. The eyes were fixed for ONL thickness analysis from histological sections or total RNA prepared for RT-PCR analysis.

 

Results

 

RESULTS: A single IVT dose of P23H ASO at 50 ug resulted in 57±8% inhibition of the P23H rho mRNA at 30 d while the control ASO had no effect. In P23H homozygote mice (various ages), this single dose of P23H ASO resulted in 57±7% preservation of the ONL layer when compared to the contralateral eye (CLE) at 60 d after treatment. Similar effects were seen in all age groups studied (1-3 months of age at the time of treatment). Eyes injected with P23H ASO had significantly more mouse rhodopsin mRNA (200 ± 18%) vs. CLE and a 47±7% increase in mouse to human rhodopsin ratio as compared to control ASO which are consistent with the presence of larger numbers of photoreceptor cells.

 

Conclusions

 

Altering the ratio of mutant to wild type rhodopsin is an effective method of photoreceptor cell preservation and treatment for P23H ADRP. This is highlighted by age and degenerative state independent increases in ONL survival observed in these studies. Further, long duration of action of ASOs (>60 days) provide a potential added benefit of less frequent dosing in patients.