Second generation anti-sense oligonucleotides show efficacy in dominant retinitis pigmentosa (RP) model.

Results from collaborative research between Isis Pharmaceuticals, the University of California at San Francisco and GlaxoSmithKlein UK, has shown that second generation anti-sense molecules targeting mutated alleles in a dominant model of retinitis pigmentosa (RP) are capable of preserving photoreceptor cell function. While similar allele selective anti-sense and ribozyme strategies were tested in the late 1990s and early 2000s, the authors of the current study claim that second generation moieties may be significantly more advantageous. Second generation anti-sense oligonucleotides have a longer half-life and may be delivered intravitreally in an aqueous-based solution making them an attractive opportunity for pharmacological intervention.


The research, based in Carlsbad, California, used chemically modified oligonucleotides to target mouse rhodopsin mRNA in the photoreceptors of a Pro23His transgenic rat model of retinitis pigmentosa. Intravitreal injection of the modified oligonucleotides showed that the anti-sense moieties were capable of accessing several retinal cell layers without the need of a viral vector delivery system, popular among several other research groups in the field. Injection of oligonucleotides targeting the mutant mouse mRNA rhodopsin within the P23H rat transgenic RP model showed allele selective targeting as the design of the anti-sense, according to the researchers, is capable of discriminating a single base-pair difference in two otherwise identical transcripts. Treated eyes had a 181 ± 39% better maximum amplitude response (scotopic a-wave) when compared with contralateral PBS-injected eyes which acted as the control. In addition, histological analysis of the outer nuclear layers (ONL) in treated animals showed significantly more thickness than untreated contralateral controls and there appeared to be a correlation between electroretinogram (ERG) response and ONL thickness.


The research represents an interesting departure from the current trend for ever more sophisticated “gene-editing” technologies, such as siRNA and CRISPR. While these later techniques may well prove to be highly efficient in the clinic, an anti-sense oligonucleotide approach also holds considerable therapeutic promise. The second generation molecules have a half-life of up to 44 days in rabbit eyes suggesting the potential for quarterly administration in humans which is less frequent than some current anti-VEGF regimens. The delivery to all cell layers and penetration of photoreceptor cells removes the necessity for viral vector delivery in a surgical setting, potentially facilitating a simpler out-patient procedure. Finally, other studies have indicated that changing the ratio of normal to dominant transcripts in a dominant negative disease environment may be sufficient to effect clinically meaningful rescue. As concluded by the authors in their paper, “we achieved a 30% reduction in mutant rhodopsin expression and no reduction in the normal rat rhodopsin expression through allele-specific antisense targeting. This reduction results in an increase in the amount of normal to mutant rhodopsin expression supporting a slower rate of photoreceptor degeneration as demonstrated by ONL and ERG analyses.”