Advancements in ocular gene therapy delivery: vectors and subretinal, intravitreal, and suprachoroidal techniques

ABSTRACT

Introduction

Ocular gene therapy represents fertile ground for rapid innovation, with ever-expanding therapeutic strategies, molecular targets, and indications.

Areas covered

Potential indications for ocular gene therapy have classically focused on inherited retinal disease (IRD) but more recently include acquired retinal diseases, such as neovascular age-related macular degeneration, geographic atrophy, and diabetic retinopathy. Ocular gene therapy strategies have proliferated recently, and include gene augmentation, gene inactivation, gene editing, RNA modulation, and gene-independent gene augmentation. Viral vector therapeutic constructs include adeno-associated virus and lentivirus and continue to evolve through directed evolution and rationale design. Ocular gene therapy administration techniques have expanded beyond pars plana vitrectomy with subretinal injection to intravitreal injection and suprachoroidal injection.

Expert opinion

The success of treatment for IRD, paired with the promise of clinical research in acquired retinal diseases and in administration techniques, has raised the possibility of in-office gene therapy for common retinal disorders within the next 5 to 10 years.

KEYWORDS:

• Gene therapy
• genome editing
• inherited retinal disease
• intravitreal
• non-viral gene therapy
• subretinal
• suprachoroidal

Article highlights

• The retina provides a unique opportunity for gene therapy given the monogenic nature of most inherited retinal diseases (IRDs), accessibility via various delivery approaches, and well-described imaging features for disease monitoring.

• Clinical trials are currently underway for a number of monogenic IRDs, including achromatopsia, choroideremia, Leber congenital amaurosis, retinitis pigmentosa (various genetic targets), Stargardt disease, and X-linked retinoschisis

• For acquired retinal diseases, the most common approach has been to generate endogenous production of therapeutic proteins targeting well-established pathways, such as anti-VEGF proteins.

• Ocular gene therapy strategies include gene augmentation for autosomal recessive monogenic disorders, in which absent or deficient production of protein occurs. Treatment leads to the constitutive expression of this gene, replacing the absent or insufficient protein and delaying degeneration. Gene augmentation has also been employed in acquired diseases where native cells ultimately produce non-native therapeutic proteins. Gene inactivation is considered for autosomal dominant disorders, with gain-of-function mutations. Other gene therapy strategies include gene editing, RNA modulation, and gene-independent gene augmentation.

• Viral vector therapeutic constructs include adenovirus, adeno-associated virus (AAV), and lentivirus. Newer-generation AAVs have been developed through directed evolution or rational design, with the goal of bypassing the internal limiting membrane (ILM), as well as generating less immunogenicity.

• The most commonly utilized administration method is pars plana vitrectomy, creation of a retinotomy, and injection of the vector into the subretinal space. Other ocular gene therapy administration techniques include intravitreal injection and suprachoroidal injection, both of which are office-based.

This box summarizes key points contained in the article.

Declaration of interest

K Kovacs is a consultant for Intergalactic Therapeutics and was previously a consultant for Regenxbio Inc. S Kiss owns intellectual property related to ocular gene therapy and cellular therapy and has acted as a consultant for Adverum, Gyroscope Therapeutics, Regenxbio Inc., and Spark Therapeutics. T Ciulla has received employee equity from Clearside Biomedical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.