Recent years have seen oligonucleotides (oligos) emerge as important therapeutic agents for treating numerous ocular diseases that previously lacked effective treatment options. Therapeutic modulation of gene expression through oligonucleotides has created novel treatment possibilities for retinal diseases such as X-linked retinitis pigmentosa (RP), Usher syndrome, and Leber's congenital amaurosis while also addressing common ocular disorders like age-related macular degeneration (AMD), dry eye syndrome (DES), and corneal diseases. Novel treatment opportunities have emerged from the use of oligos as viable therapies, but their broad clinical adoption faces substantial challenges.
Oligonucleotides function as short synthetic nucleic acid polymers that bind to specific RNA sequences to regulate gene expression through inhibition or activation. Oligos offer precision medicine benefits by directly targeting genetic material to repair mutations at the molecular level while treating ocular diseases. Research and development in ocular therapeutics now focuses intensively on the effective delivery of oligonucleotides to the eye.
Oligos possess exceptional molecular characteristics, which position them as strong candidates for ocular gene therapy solutions. This precision enables oligos to treat genetic diseases that target retinal cells and offers additional benefits for other conditions caused by abnormal gene expression, including AMD.
Figure 1. Antisense oligonucleotides for the treatment of retinitis pigmentosa caused by USH2A exon 13 mutations[1].
The eye's anatomical and physiological traits create multiple obstacles for successful delivery of oligonucleotide-based treatments. The blood-retinal barrier (BRB) stands as one major obstacle alongside the need for drug stability and effective cellular uptake. Oligonucleotides struggle to penetrate ocular barriers, leading to reduced bioavailability and therapeutic effectiveness when delivered via topical or systemic application.
The molecular size of oligonucleotides presents a major hurdle in drug delivery. The size of these molecules surpasses that of typical drug compounds, resulting in obstacles during their penetration into retinal tissues. Because the eye is divided into compartments, the treatment of specific areas in the retina or cornea needs higher doses of therapy, which may lead to toxic effects unless dosage is meticulously managed. We need to develop delivery systems that improve the transport of oligos to their target tissues at proper therapeutic levels.
Multiple delivery methods for eye-targeted oligonucleotides are under study as each presents distinct benefits and drawbacks.
The topical delivery method through eye drops stands out as the most convenient treatment approach for anterior segment diseases, including dry eye syndrome and conjunctivitis. Eye drops fail to deliver adequate treatment for posterior segment conditions like AMD or RP because they do not penetrate well and have low bioavailability. The cornea and retina face a substantial loss of medication caused by the eye's tear film and fast drug drainage.
Intraocular injections serve as the preferred treatment method for posterior segment diseases because they allow direct drug delivery to the retina, which results in higher local drug concentrations. This method enhances bioavailability and cellular targeting capabilities but introduces complications like inflammation along with immune responses and heightened infection risks. Accurate dosing of oligonucleotides is essential for preventing harmful effects like retinal damage or endophthalmitis.
Scientific research examines lipid nanoparticles and viral vectors as potential means to enhance oligo-delivery systems. These delivery systems work to stabilize drugs while improving cellular uptake and enabling blood-retinal barrier penetration. Researchers modify oligo backbones and conjugate targeting ligands to enhance delivery system precision and efficiency.
Figure 2. Schematic representation of various formulation approaches and routes of administration to the ocular tissues[2].
Drug efficacy and pharmacokinetics evaluation in ocular delivery of oligonucleotides requires precise bioanalytical methods, which adds to the logistical challenges. The ADME properties of oligos within ocular tissues require assessment through multiple techniques.
In Vitro Methods
Oligos require in vitro assays to determine their stability and binding capabilities. The tests performed include serum/plasma stability assessments, plasma protein binding analyses, and detection of metabolites within specific target tissues, including the liver and retina.
In Vivo Methods
The distribution and clearance of oligonucleotides post-administration must be assessed through in vivo PK studies. Scientists perform these studies using animal models such as rabbits and non-human primates (NHPs) to measure oligo concentrations in ocular tissues as well as systemic circulation and excretory routes like urine, feces, and bile.
Bioanalytical characterization typically involves mass spectrometry (MS), quantitative PCR (qPCR), and fluorescent techniques. The techniques enable researchers to measure oligonucleotide amounts accurately within biological matrices and also reveal essential information about their stability and distribution patterns in eye tissues.
Preclinical testing of oligonucleotides for eye diseases utilizes animal models whose ocular structure closely matches that of humans. Initial studies to evaluate drug distribution and toxicity prefer rabbits because their eyes are relatively large. Non-human primates (NHPs) stand out as the best models because their ocular anatomy and physiology closely match human characteristics.
During preclinical testing, oligos are delivered through injections or embedded devices to reach specific regions within the eye. Researchers examine how tissue distribution and clearance occur and investigate potential systemic effects. Researchers aim to localize the oligonucleotide exclusively within the eye to avoid systemic circulation and reduce potential toxicity to other organs.
Researchers use in vivo studies to test various delivery methods and optimize dosage procedures. Scientific research has shown that specific drug delivery systems like lipid nanoparticles boost both penetration into and retention within the eye, which leads to better therapeutic results.
Advancements in oligonucleotide-based ocular therapies have been made, but their regulatory development still faces multiple obstacles. Regulatory bodies must establish detailed guidelines for oligo formulations and their dosing regimens, as well as delivery methods. Without established standards, developers struggle during approval procedures, which slows down the introduction of new therapies.
The intricate properties of oligonucleotide formulations, along with delivery challenges to ocular tissues, demand extensive testing. Before clinical approval can be granted, regulatory bodies like the FDA need to evaluate the safety, efficacy, and stability of these treatments. Alfa Chemistry excels in creating chemical compounds to support oligo-based therapeutics by offering superior oligos and delivery systems intended for research applications.
| Project Number | Indication |
| ONT-ED001 | NAION |
| ONT-ED002 | Glaucoma |
View our developing products for eye diseases.
References
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