Therapy For Ocular Diseases Research Articles

A Paradigm Shift in Ocular Drug Delivery to Posterior Segment: Review on Current Drug Delivery Approaches

Objectives: Owing to the increasing number of patients suffering from posterior eye disorders, efficient medicine delivery to the posterior segment is now in great demand in the clinical services. With unmet medical requirements, the posterior eye segment is an important therapeutic target. So, physicians should be informed of new indications and current strategies of drug delivery when new technologies enter the market.
 Summary: The most common causes of vision impairment in developed nations are abnormalities of the posterior eye tissues. Poor drug distribution to lesions in patient's eyes is a key barrier to ocular disease therapy. The existence of barriers, such as the corneal barrier, aqueous barrier, and inner and outer blood-retinal barriers, severely limits medication accessibility in these locations. Because of its anatomical peculiarities, the posterior portion is particularly difficult to access for medications. The use of several new strategies for drug delivery is therefore a viable option for enhanced therapy of ocular disorders since recent advances in ocular drug delivery systems research have brought fresh insights into drug development.
 Conclusion: This article provides an overview of several aspects of ocular medication administration to the posterior region, with a focus on nano carrier-based approaches, suprachoroidal drug delivery system and ophthalmic devices, including the structure of the eye, its barriers, delivery routes, and the present status of drugs/devices.

HIF Inhibition Therapy in Ocular Diseases

The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which anti-VEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases.

Mitophagy: An Emerging Target in Ocular Pathology.

Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.

SiRNA Therapeutics in Ocular Diseases.

The field of RNAi therapeutics has quickly adapted to the treatment of ocular diseases. Although the eye provides a unique system for the delivery of siRNAs, its complex structure and composition fostered the development of novel strategies for efficient gene silencing in the target compartment. Moreover, anterior and posterior segments differ in their multiple drug barriers and clearance mechanisms. This chapter summarizes the recent achievements in terms of routes of administration, chemical modifications, and delivery systems for siRNAs that specifically apply to eye disorders. Methods employed for siRNA detection/quantitation in ocular tissues are also described, together with safety concerns that need to be addressed to fulfill regulatory requirements of new drug approval. Even though RNAi therapies for ocular diseases have not yet translated into patient care, we document herein the rising number of candidate drugs currently under preclinical or clinical development.

An Endostatin-lentivirus (ES-LV)-EPC gene therapy agent for suppression of neovascularization in oxygen-induced retinopathy rat model

BackgroundTransplantation of gene transfected endothelial progenitor cells (EPCs) has provided novel methods for tumor neovascularization therapy but not for ocular disease therapy. This study aimed to investigate the efficacy of endostatin transfected EPCs in retinal neovascularization therapy.ResultsQuantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed the high expression of endostatin in endostatin-lentivirus-EPCs. The neovascularization leakage area and the number of preretinal neovascular cell nuclei were significantly decreased in the endostatin-lentivirus and endostatin-lentivirus-EPC groups, and the effects of these two treatments on inhibiting retinal neovascularization were almost the same. These two groups also showed the greater retinal distribution of endostatin. Intravitreal injections of endostatin-lentivirus-EPCs inhibited retinal neovascularization, vascular endothelial growth factor (VEGF) and CD31 expression, and increased endostatin expression in vivo. Endostatin-lentivirus-EPCs targeted and prevented pathologic retinal neovascularization.ConclusionsGene-combined EPCs represent a potential new therapeutic agent for the treatment of neovascular eye diseases.

Plasmacytoid dendritic cells in the eye.

Plasmacytoid dendritic cells (pDCs) are a unique subpopulation of immune cells, distinct from classical dendritic cells. pDCs are generated in the bone marrow and following development, they typically home to secondary lymphoid tissues. While peripheral tissues are generally devoid of pDCs during steady state, few tissues, including the lung, kidney, vagina, and in particular ocular tissues harbor resident pDCs. pDCs were originally appreciated for their potential to produce large quantities of type I interferons in viral immunity. Subsequent studies have now unraveled their pivotal role in mediating immune responses, in particular in the induction of tolerance. In this review, we summarize our current knowledge on pDCs in ocular tissues in both mice and humans, in particular in the cornea, limbus, conjunctiva, choroid, retina, and lacrimal gland. Further, we will review our current understanding on the significance of pDCs in ameliorating inflammatory responses during herpes simplex virus keratitis, sterile inflammation, and corneal transplantation. Moreover, we describe their novel and pivotal neuroprotective role, their key function in preserving corneal angiogenic privilege, as well as their potential application as a cell-based therapy for ocular diseases.

Tissue-Derived Biological Particles Restore Cornea Properties in an Enzyme-Mediated Corneal Ectatic Model.

Purpose: To investigate the impact of tissue derived biological particles on enzyme-mediated weakened corneas. Methods: Rabbit corneas were treated with enzymes to create an ex vivo ectatic model that simulated representative characteristics of keratoconus (KC). Porcine cornea, cartilage, and lymph node tissues were processed to remove most cellular components and cryomilled into microparticles. The KC corneas were cultured in medium containing the tissue-derived biological particles (TDP) overnight. The mechanical, thermal, ultrastructural changes, and gene expressions of corneal stromal cells were characterized to evaluate the effects of the TDP treatment. Results: The enzyme treatment significantly reduced corneal mechanics and thermal stability, and also disrupted the extracellular matrix ultrastructure. After culturing with TDP medium, the Young’s modulus of the modeled KC corneas increased by ~50%, comparable to normal cornea controls. Similarly, the thermal denaturation temperature of the corneas was restored. These findings also corresponded to a significant increase in collagen fibril density after TDP treatment. Furthermore, corneas cultured in TDP medium significantly downregulated expression of the pro-inflammatory gene Tnfα, and restored the expression of the key keratocyte markers Aldh, keratocan, and biglycan. Conclusions: Tissue-derived biological particles reinforce mechanical and thermal properties of corneal tissue in an ex vivo model of KC. Through this study, we demonstrate and characterize the previously unexplored impact of tissue-derived biological scaffolds on corneal biomechanics, thermal stability, and gene expression, presenting a potential new therapy for ocular disease.

Occular Drug Delivery System – A Review

The unique Anatomy of the eye makes it a highly protected organ and unique structure restricts entry of the drug into the target site of action. Designing an effective therapy for ocular diseases has been considered as a difficult task. Major barriers in eye medication are the ability to maintain a therapeutic level of the drug at the site of action. Therapeutic drug levels are not maintained for a longer duration in target tissues. Limitations of the traditional route of administration have challenged scientists to find an alternative mode of administration like periocular routes. The ophthalmic formulations are available as buffered, isotonic, sterile solution. A number of types of dosage forms are applied as the drug delivery system for the ocular delivery. The topical ocular drop is the most suitable and patient compliant route of drug administration, especially for the management of anterior segment diseases. Ideal ophthalmic drug formulation must be able to prolong the drug release and to remain in the area of the front of the eye for prolong period. It is necessary to optimize ophthalmic drug delivery; one way to do so is by adding polymers, development of in situ gel or using erodible or nonerodible insert orcolloidal suspension to extend the precorneal drug retention.

Highly bioactive, bevacizumab-loaded, sustained-release PLGA/PCADK microspheres for intravitreal therapy in ocular diseases

Bevacizumab, a vascular endothelial growth factor (VEGF)-targeting drug, is widely used as an off-label therapeutic for age-related macular degeneration (AMD). To reduce the monthly administration frequency, this study investigated microspheres comprising a poly(d, l-lactide-co-glycolide)/poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PLGA/PCADK) blend that could be loaded with bevacizumab-dextran particles using solid-in-oil-in-water (S/O/W) emulsification. Control microspheres were also prepared through water-in-oil-in-water (W/O/W) emulsification. The structural stability of bevacizumab in the polymer monomers was analyzed using dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size exclusion chromatography (SEC-HPLC), circular dichroism (CD) and fluorescence spectroscopy. Subsequently, microspheres were prepared and evaluated in terms of their morphology, encapsulation efficiency and release behavior. PLGA/PCADK microspheres prepared by the S/O/W method with <20% PCADK showed a smooth spherical structure with a uniform distribution of bevacizumab. The microspheres exhibited a release behavior comprising a slight initial burst and an increasing total release over 50 days both in vitro and in vivo. Additionally, the microspheres were well tolerated by ocular tissue. Finally, a chorioallantoic membrane (CAM) assay revealed that the bioactivity of bevacizumab was retained by PCADK. In conclusion, these results suggest the potential for bevacizumab-loaded PLGA/PCADK microspheres prepared by the S/O/W method as a means of intravitreal therapy for ocular diseases.

Non-coding RNAs in retinal development and function.

Accumulating evidence on the role of non-protein-coding RNA sequences in the regulation of gene expression is greatly expanding our understanding of the flow of genetic information within biological systems. The interplay between protein-coding and non-coding RNAs (ncRNAs) is essential for tissue development, homeostasis, and function. NcRNAs can be divided in short ncRNAs, whose main subtype is represented by microRNAs, and long ncRNAs, which constitute a more heterogeneous class. The retina is a light-sensitive tissue consisting of highly interconnected cell types and is the primary target of many genetic diseases. Among these, the genetically heterogeneous group of inherited retinal diseases (IRDs) represents the most frequent monogenic cause of visual impairment that can ultimately lead to blindness. Here, we provide an overview on the role of ncRNAs in retinal development and function with an emphasis on microRNAs and on different types of long ncRNAs. We also review how sequence variations in ncRNAs can play a pathogenic role in IRDs as well as in multifactorial ocular disorders. These data indicate that a comprehensive study of the contribution of ncRNAs to the mutation repertoire associated with retinal disease can shed light on previously unknown pathophysiological mechanisms and open new therapeutic avenues. We conclude that a more comprehensive dissection of the pathogenic role of non-coding RNAs in retinal function and disease will not only improve our diagnostic ability, but will allow the development of novel targeted therapies for ocular disease.

Gene therapy for visual loss: Opportunities and concerns.

Many clinical trials using gene therapy have shown significant therapeutic benefits and exceptional safety records. Increasing evidence is verifying the long sought-after promise that gene therapy will genetically 'cure' some severely disabling diseases. In particular, the first gene therapy bioproduct for RPE65-associated Leber's congenital amaurosis, which was approved by the US Food and Drug Administration in 2017, has provided tremendous encouragement to the field of gene therapy. Recent developments in genome editing technologies have significantly advanced our capability to precisely engineer genomes in eukaryotic cells. Programmable nucleases, particularly the CRISPR/Cas system, have been widely adopted in studies applying genome engineering therapy to ocular diseases with the hope of managing these diseases. In this review article, we summarize the current approaches that have been developed in the area of gene therapy for ocular disease. We also discuss the challenges and opportunities facing gene therapy for ocular diseases, as well as its prospects.

Inner layer-embedded contact lenses for ion-triggered controlled drug delivery

Drug leakage during manufacturing and storage process is the main obstacle hindering the application of contact lenses as the carrier for extended ocular drug delivery. In this study, we have designed a novel inner layer-embedded contact lens capable of ion-triggered drug release for extended ocular drug delivery. Using betaxolol hydrochloride as a drug model, drug-ion exchange resin complex dispersed polymer film was used as an inner layer, and silicone hydrogel was used as an outer layer to fabricate inner layer-embedded contact lens. Influence of composition of the inner film and crosslinking degree of the outer hydrogel on drug release profile was studied and optimized for weekly use. The ion-triggered drug eluting property enables the inner layer-embedded contact lens being stable when stored in distilled water at 5 °C for at least 30 days with ignorable drug loss and negligible changes in drug release kinetics. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 168 h in tear fluid, indicating significant improvement in drug corneal residence time. A level A IVIVC was established between in vitro drug release and in vivo drug concentration in tear fluid. In conclusion, this inner layer embedded contact lens design could be used as a platform for extended ocular drug delivery with translational potential for both anterior and posterior ocular disease therapy.

A scalable and deformable stylized model of the adult human eye for radiation dose assessment

With recent changes in the recommended annual limit on eye lens exposures to ionizing radiation, there is considerable interest in predictive computational dosimetry models of the human eye and its various ocular structures including the crystalline lens, ciliary body, cornea, retina, optic nerve, and central retinal artery. Computational eye models to date have been constructed as stylized models, high-resolution voxel models, and polygon mesh models. Their common feature, however, is that they are typically constructed of nominal size and of a roughly spherical shape associated with the emmetropic eye. In this study, we present a geometric eye model that is both scalable (allowing for changes in eye size) and deformable (allowing for changes in eye shape), and that is suitable for use in radiation transport studies of ocular exposures and radiation treatments of eye disease. The model allows continuous and variable changes in eye size (axial lengths from 20 to 26 mm) and eye shape (diopters from −12 to +6). As an explanatory example of its use, five models (emmetropic eyes of small, average, and large size, as well as average size eyes of −12D and +6D) were constructed and subjected to normally incident beams of monoenergetic electrons and photons, with resultant energy-dependent dose coefficients presented for both anterior and posterior eye structures. Electron dose coefficients were found to vary with changes to both eye size and shape for the posterior eye structures, while their values for the crystalline lens were found to be sensitive to changes in only eye size. No dependence upon eye size or eye shape was found for photon dose coefficients at energies below 2 MeV. Future applications of the model can include more extensive tabulations of dose coefficients to all ocular structures (not only the lens) as a function of eye size and shape, as well as the assessment of x-ray therapies for ocular disease for patients with non-emmetropic eyes.

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

Background/Aims: Lipocalin 2 (LCN2), an important mediator of a variety of cellular processes, is involved in regulating the inflammatory response, but its roles in different inflammatory diseases are controversial. Because the role of LCN2 in ocular inflammation has been unclear until now, we explored the function of LCN2 in lipopolysaccharide (LPS)-induced ocular inflammation in vivo and in vitro. Methods: Endotoxin-induced uveitis (EIU) was induced in male Sprague Dawley rats by the intravitreal injection of LPS. The expression and location of LCN2 in the retina were detected with western blotting and immunohistochemistry, respectively. We determined the clinical scores for anterior inflammation, quantified the infiltrated inflammatory cells, and measured the pro-inflammatory factors to determine the anti-inflammatory effects of LCN2 in EIU eyes. Cultured primary rat Müller cells were stimulated with LPS and the expression and secretion of LCN2 were measured with real-time PCR, western blotting, and an ELISA. After Müller cells were cotreated with LPS and LCN2 or PBS, the expression and secretion of TNF-α, IL-6, and MCP-1 were examined with realtime PCR, western blotting, and ELISAs. Western blotting and immunofluorescence were used to detect the phosphorylation and cellular distribution of nuclear factor kappaB (NF-κB) subunit p65. Results: In EIU, the expression of LCN2 was significantly upregulated in the retina, especially in the outer nuclear layer (mainly composed of Müller cells). LPS stimulation of cultured Müller cells also markedly elevated LCN2 expression. Intravitreal injection of LCN2 significantly reduced the clinical scores, inflammatory infiltration, and protein leakage in EIU, which correlated with the reduced levels of proinflammatory factors in the aqueous humor and retina. LCN2 treatment also reduced the expression and secretion of TNF-α, IL-6, and MCP-1 in LPS-stimulated Müller cells. LCN2 inhibited the inflammatory response by inhibiting the phosphorylation and translocation of NF-κB p65. Conclusions: LCN2 protects against ocular inflammation, at least in part, by negatively regulating the activation of the NF-κB signaling pathway. LCN2 may be a promising anti-inflammatory therapy for ocular diseases, such as uveitis.

The association between nuclear receptors and ocular diseases.

Nuclear hormone receptors (NRs) are one of the most abundant transcription factors in the human cells. They regulate expression of genes via interactions with corresponding ligands, co-activators, and co-repressors. These molecular pathways play important roles in the development, cell differentiation, and physiologic and metabolic processes. Increasingly, targeting nuclear receptors is becoming a promising strategy for new drug development. The aim of this review is to discuss the association between nuclear receptors and eye development, and expand their role in various ocular diseases such as keratitis, cataract, glaucoma, uveitis, retinopathy, and ophthalmic tumors. Recent studies in this area are highlighted as well as future research directions and potential clinical applications. Finally, various strategies will be elucidated to inspire more targeted therapies for ocular diseases through the use of nuclear receptors.

Genomic Disruption of VEGF-A Expression in Human Retinal Pigment Epithelial Cells Using CRISPR-Cas9 Endonuclease.

PurposeTo employ type II clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonuclease to suppress ocular angiogenesis by genomic disruption of VEGF-A in human RPE cells.MethodsCRISPR sequences targeting exon 1 of human VEGF-A were computationally identified based on predicted Cas9 on- and off-target probabilities. Single guide RNA (gRNA) cassettes with these target sequences were cloned into lentiviral vectors encoding the Streptococcus pyogenes Cas9 endonuclease (SpCas9) gene. The lentiviral vectors were used to infect ARPE-19 cells, a human RPE cell line. Frequency of insertion or deletion (indel) mutations was assessed by T7 endonuclease 1 mismatch detection assay; mRNA levels were assessed with quantitative real-time PCR; and VEGF-A protein levels were determined by ELISA. In vitro angiogenesis was measured using an endothelial cell tube formation assay.ResultsFive gRNAs targeting VEGF-A were selected based on the highest predicted on-target probabilities, lowest off-target probabilities, or combined average of both scores. Lentiviral delivery of the top-scoring gRNAs with SpCas9 resulted in indel formation in the VEGF-A gene at frequencies up to 37.0% ± 4.0% with corresponding decreases in secreted VEGF-A protein up to 41.2% ± 7.4% (P < 0.001), and reduction of endothelial tube formation up to 39.4% ± 9.8% (P = 0.02). No significant indel formation in the top three putative off-target sites tested was detected.ConclusionsThe CRISPR-Cas9 endonuclease system may reduce VEGF-A secretion from human RPE cells and suppress angiogenesis, supporting the possibility of employing gene editing for antiangiogenesis therapy in ocular diseases.

Ocular Purine Receptors as Drug Targets in the Eye.

Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A1, A2A, and A3. An A1AR agonist is in clinical trials for glaucoma, A2AAR reduces neuroinflammation, A3AR protects retinal ganglion cells from apoptosis, and both A3AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y2 and P2Y6, lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

Drug discovery in ophthalmology: past success, present challenges, and future opportunities.

BackgroundDrug discovery has undergone major transformations in the last century, progressing from the recognition and refinement of natural products with therapeutic benefit, to the systematic screening of molecular libraries on whole organisms or cell lines and more recently to a more target-based approach driven by greater knowledge of the physiological and pathological pathways involved. Despite this evolution increasing challenges within the drug discovery industry are causing escalating rates of failure of development pipelines.DiscussionWe review the challenges facing the drug discovery industry, and discuss what attempts are being made to increase the productivity of drug development, including a refocusing on the study of the basic biology of the disease, and an embracing of the concept of ‘translational research’. We consider what ophthalmic drug discovery can learn from the sector in general and discuss strategies to overcome the present limitations. This includes advances in the understanding of the pathogenesis of disease; improvements in animal models of human disease; improvements in ophthalmic drug delivery and attempts at patient stratification within clinical trials.SummaryAs we look to the future, we argue that investment in ophthalmic drug development must continue to cover the whole translational spectrum (from ‘bench to bedside and back again’) with recognition that both biological discovery and clinical understanding will drive drug discovery, providing safe and effective therapies for ocular disease.

Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors.

The use of angiotensin receptor blockers (ARBs) for treatment of ocular diseases associated with neovascularizations, such as proliferative diabetic retinopathy, shows tremendous promise but is presently limited due to short intravitreal half-life. Conjugation of ARB molecules to branched polymers could vastly augment their therapeutic efficacy. EXP3174, a potent non-peptide ARB, was conjugated to branched poly(ethylene glycol) (PEG) and poly(amido amine) (PAMAM) dendrimers: 7.8 ligand molecules were tethered to each 40 kDa PEG molecule whereas 16.7 ligand molecules were linked to each PAMAM generation 5 dendrimer. The multivalent PEG and PAMAM conjugates blocked AT1R signaling with an IC50 of 224 and 36.3 nM, respectively. The 6-fold higher affinity of the multivalent ligand-conjugated PAMAM dendrimers was due to their unique microarchitecture and ability to suppress polymer-drug interactions. Remarkably, both polymer-drug conjugates exhibited no cytotoxicity, in stark contrast to plain PAMAM dendrimers. With sufficiently long vitreous half-lives, both synthesized polymer-ARB conjugates have the potential to pave a new path for the therapy of ocular diseases accompanied by retinal neovascularizations.

Gene therapy for ocular diseases meditated by ultrasound and microbubbles (Review).

The eye is an ideal target organ for gene therapy as it is easily accessible and immune-privileged. With the increasing insight into the underlying molecular mechanisms of ocular diseases, gene therapy has been proposed as an effective approach. Successful gene therapy depends on efficient gene transfer to targeted cells to prove stable and prolonged gene expression with minimal toxicity. At present, the main hindrance regarding the clinical application of gene therapy is not the lack of an ideal gene, but rather the lack of a safe and efficient method to selectively deliver genes to target cells and tissues. Ultrasound-targeted microbubble destruction (UTMD), with the advantages of high safety, repetitive applicability and tissue targeting, has become a potential strategy for gene- and drug delivery. When gene-loaded microbubbles are injected, UTMD is able to enhance the transport of the gene to the targeted cells. High-amplitude oscillations of microbubbles act as cavitation nuclei which can effectively focus ultrasound energy, produce oscillations and disruptions that increase the permeability of the cell membrane and create transient pores in the cell membrane. Thereby, the efficiency of gene therapy can be significantly improved. The UTMD-mediated gene delivery system has been widely used in pre-clinical studies to enhance gene expression in a site-specific manner in a variety of organs. With reasonable application, the effects of sonoporation can be spatially and temporally controlled to improve localized tissue deposition of gene complexes for ocular gene therapy applications. In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood-retinal barrier with no significant side effects. The present review discusses the current status of gene therapy of ocular diseases as well as studies on gene therapy of ocular diseases meditated by UTMD.