Español
Antisense oligonucleotides (ASOs) are small synthetic nucleic acid sequences that have the potential to transform the treatment of genetic and multifactorial eye diseases previously considered untreatable.
What are ASOs and why are they so promising?
ASOs are short, synthetic strands of DNA or RNA that bind to messenger RNA (mRNA) to modulate gene expression. Thanks to their ability to act at the RNA level , they can silence disease-causing genes without altering other cellular functions.
This makes them high-precision tools for the treatment of diseases such as retinitis pigmentosa, macular degeneration, glaucoma, Usher syndrome and Leber congenital amaurosis ( LCA ), all of which are characterised by their genetic origin and, in many cases, by the lack of effective therapies so far.
ASOs act through various mechanisms that allow them to intervene directly at the RNA level: they can induce mRNA degradation before it is translated into pathological proteins, correct errors in the splicing process to restore the production of functional proteins, block translation to prevent the synthesis of defective proteins, or even act in an allele-specific manner, i .e. target the mutation exclusively without interfering with the normal copy of the gene.
Challenges in its development
Despite their enormous potential, the development of antisense oligonucleotides for the treatment of eye diseases faces several challenges, particularly with regard to their delivery. The eye is an anatomically and physiologically complex environment, with barriers such as the cornea, the blood-retinal barrier and the retinal pigment epithelium, which make it difficult for the drug to reach its destination. Currently, the most commonly used route is intravitreal injection with eye drops, which allows high local concentrations to be achieved in the retina, but is an invasive procedure that is not without risk. To overcome these limitations, sustained release formulations and nanoparticle-based systems are being developed with the aim of improving safety, efficacy and reducing the frequency of administration.
Although no ASO is yet approved specifically to treat inherited retinal diseases, several candidates are in late-stage clinical trials. Sepofarsen, for example, targets a form of Leber congenital amaurosis ( LCA10) linked to the CEP290 gene or QR-1123 targets a specific mutation in the RHO gene associated with an autosomal dominant form of the latter disease.
Although the regulatory framework for antisense oligonucleotides is still evolving, agencies such as the FDA have already begun to establish preliminary guidelines for their non-clinical evaluation, especially with regard to immunological safety. In this regard, the eye offers an important advantage for the development of ASO therapies as it possesses special mechanisms to limit the immune response, thus protecting its tissues from inflammation.
Although their clinical implementation still requires overcoming scientific, technological and regulatory barriers, their potential to offer solutions to currently incurable diseases makes them one of the most promising bets for the future of ocular therapeutics.
Sources
REVOLUTIONISING EYE CARE: THE POTENTIAL OF ANTISENSE OLIGONUCLEOTIDES – ONdrugDelivery
