Ocular Gene Therapy with Adeno-associated Virus Vectors

Overview of Ocular Disorders

Millions of people worldwide suffer from eye disorders that can result in severe vision impairment or blindness. These include multifactorial diseases such as glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy, and inherited diseases such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA) and achromatopsia. Most of these diseases do not have effective treatment options. The progress in gene therapy has brought great hope for the management of ophthalmic conditions, and ocular gene therapy has been extensively explored in recent years as a therapeutic avenue to target diseases of the retina, cornea and retinal pigment epithelium (RPE). So far, more than forty clinical protocols of ocular gene therapy are being (or have been) tested in human patients, and many more are in the preclinical phase of development.

Vectors for Ocular Gene Delivery

Gene therapy, which involves intracellular delivery of genetic material to block a dysfunctional gene or to deliver a gene as a therapeutic means, has great potential for treating diseases with a genetic component. The success of gene therapy depends on the efficient delivery of the genetic material to target cells, achieving optimal long-term gene expression. A variety of non-viral and viral vector systems have been evaluated for retinal gene transfer, including nanoparticles, adenovirus, lentivirus, and adeno-associated virus (AAV). AAV has been proved to be the most suitable vector for efficient and long-term expression in retinal cells. Naturally occurring AAVs are very efficient in transducing photoreceptors, retinal pigment epithelial (RPE) cells, Müller glia or RGCs. In addition, novel engineered AAV vectors now also allow for targeting almost any retinal cell type. Notably, voretigene neparvovec (Luxturna), an AAV vector delivering the human RPE65 gene for the treatment of type 2 Leber congenital amaurosis (LCA2), has been approved by the Food and Drug Administration (FDA) as the first in vivo gene therapy product in the United States.

Applications of AAVs in Ocular Disorders Therapy

Many AAV serotypes and variants have been tested for gene delivery to the eye through different injection routes. In the retina, subretinal administration of AAV2 vectors leads to the transduction of RPE and photoreceptor cells, whereas intravitreal injection results in ganglion cell transduction. The experience with AAVs has suggested that AAV2/5 and AAV2/8 are the two most efficient serotypes for photoreceptor targeting. However, AAVs mainly transduces rods, and gene transfer to both cones and rods is essential for gene therapy of inherited retinal degenerations such as LCA1. Recently, Manfredi et al. have demonstrated that the chimeric AAV2/8 transduces both pig cones and rods, which supports the application of AAV2/8 for gene therapy of retinal diseases. AAVs can also be used to transfect corneal cells. In primary cultures of human corneal fibroblasts exposed to different AAV infectious particles, the transfection efficiency of AAV2/6 was 30-50-fold higher than that of AAV2/8 or AAV2/9. However, when the same viral vectors were topically applied to mouse cornea in vivo and human cornea ex vivo, the order of transduction efficiency was AAV2/9 > AAV2/8 > AAV2/6. Importantly, the results of AAV were safe, and cell death or inflammation was not detected.

AAV vectors have been proved to be an effective tool for the development of curative treatments for hereditary retinal disorders. In order to treat autosomal recessive retinal disorders, AAVs are used in so-called gene supplementation approaches to transfer a wild-type copy of the mutated gene into affected retinal cells. Gene supplementation therapy was successfully conducted in patients of LCA2, a form of the disease that results in nearly total blindness in childhood. LCA2 is caused by a mutation in the gene RPE65 coding for a central protein of the retinoid cycle and the treatment involves AAV2/2 mediated delivery of the wild-type RPE65 gene. The development of the treatment began with LCA animal models and further promising human clinical trials followed. To date, treated LCA-patients show a significant visual improvement in short term and this level continues for at least 3 years after initial treatment.

Gene therapy can also be a powerful way to treat non-hereditary chronic conditions such as diabetic retinopathy and age-related macular degeneration (AMD). For the wet form of AMD characterized by macular neovascularization, bleedings and edema, the vascular endothelial growth factor (VEGF) has been identified as a key molecule affecting the pathogenic progression. Based on the discovery that VEGF promotes choroidal neovascularization, novel drugs against VEGF were developed. To date, various studies presented encouraging preclinical methods based on AAVs encoding either monoclonal antibodies, shRNAs or specific receptor domains directed against VEGF that lead to the suppression of ocular neovascularization in AMD animal models. Another gene therapeutic method in an AMD mouse model was successfully conducted applying proline/arginine-rich end leucine-rich repeat protein (PRELP) by AAVs against the complement factor H. Recently, a similar method also had a beneficial effect in a murine model of diabetic retinopathy.

QVirusTM Platform, a division of Creative Biogene, can offer a series of AAV services to accelerate your ocular disorders gene therapy projects. If you have any special requirements, please feel free to contact us.

1. Casey G A, et al. Ocular Gene Therapy with Adeno-associated Virus Vectors: Current Outlook for Patients and Researchers. Journal of Ophthalmic & Vision Research, 2020, 15(3): 396.
2. Moore N A, et al. Gene therapy for inherited retinal and optic nerve degenerations. Expert Opinion on Biological Therapy, 2018, 18(1): 37-49.
3. Yu W, Wu Z. Ocular delivery of CRISPR/Cas genome editing components for treatment of eye diseases. Advanced Drug Delivery Reviews, 2020.
4. Solinís M Á, et al. Treatment of ocular disorders by gene therapy. European Journal of Pharmaceutics and Biopharmaceutics, 2015, 95: 331-342.
5. Schön C, et al. Retinal gene delivery by adeno-associated virus (AAV) vectors: Strategies and applications. European journal of pharmaceutics and biopharmaceutics, 2015, 95: 343-352.
6. Rodrigues G A, et al. Pharmaceutical development of AAV-based gene therapy products for the eye. Pharmaceutical research, 2019, 36(2): 29.

For research use only. Not intended for any clinical use.

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