RP treatment

Therapeutic use of antisense oligonucleotides (AOs) for RHO mediated RP:

AOs are single stranded sequences of DNA or RNA that are shorter than the specific target gene sequence, and modify gene expression. 

• Dulla et al (3) used intravitreal delivery of AOs to skip exon 13 in the USH2A gene of mice, which like RHO is also associated with retinitis pigmentosa. This created a smaller functional retinal protein. 

• A similar approach could be trialed with mutated RHO, in which the removal of exon 1 for the P23H mutation of RHO could be investigated to see if the protein retains any function without the mutant exon. This could allow for production of functional or semi-functional rhodopsin that does not aggregate in the endoplasmic reticulum and cause retinal degradation. 

• AOs could also be used to bind to mRNA to prevent the process of translation of the RHO gene. If an individual who is heterozygous for RP, and has one functional copy of RHO and one mutant copy, AOs could be created specifically to target the mutant RHO mRNA, while allowing the translation functional wild type copies. This would allow for some functional rhodopsin to be produced. 

This treatment could be used for any pathogenic variants of the RHO gene, as synthetic AOs could be designed to target any specific mRNA sequence. 

Barriers include:

• Delivery of the AOs to the specific tissues (in this case, the retina), and the uptake of the AOs into the rod cells (4). The retina is a difficult tissue to manipulate, as it sits at the back of the eye. It is a fragile layer of cells, and therefore it would be difficult to inject or distribute therapeutics to this site without invasive procedures. 

• Caution must also be taken to ensure that the AOs are not able to modify the gene expression of other mRNAs for different proteins.  

As AOs are becoming recognised as a method of personalised treatment for a range of genetic disorders, it is likely this treatment will be available for those affected by RP in the near future.