Revealing the frontier: drug delivery challenges and innovations in ocular gene therapy

Ophthalmic gene therapies

Gene therapy in ophthalmology can be broadly categorised into two types:

1. Gene replacement therapies, which aim to correct defective genes in IRDs such as RPE65-related retinal dystrophy.
2. Therapeutic gene therapies, which transform the eye into a biofactory to produce therapeutic proteins, such as anti-vascular endothelial growth factor (VEGF) agents for wet AMD.

While IRDs often involve small patient populations and severe outcomes like blindness, AMD affects millions and requires scalable solutions. The delivery method must be tailored to the disease, the patient and the therapeutic goal. Vectors to deliver genetic material to cells are most often viruses, such as adeno-associated virus or lentivirus, but lipid nanoparticles (LNPs) are the subject of increasing investigations due to their lower immune reactions and potentially improved targeting. The design of gene therapy vectors is challenging in its own right and beyond the scope of this article.

Delivery routes for ophthalmic gene therapies - the trade-offs and technical barriers

Many people have at some point used an eye treatment in the form of eye drops or ocular sprays. However, vectors for gene therapy are too large to traverse the sclera to reach the deep structures of the eye, so more invasive delivery methods are required. There are four main approaches to delivery for ocular gene therapy: intravitreal therapy (IVT), subretinal (SR) delivery, implants and suprachoroidal (SC) delivery.

Intravitreal therapy

IVT has been the common choice for ocular delivery for decades and is widely used for delivering biologics like antiVEGF agents to treat AMD. It is minimally invasive, can be performed in outpatient settings, and a historically good safety profile. An IVT delivery device may be as simple as a needle and syringe, making the procedure easily accessible. However, there are challenges to efficacy of gene therapies delivered by IVT. Delivery vectors must diffuse over a considerable distance through the vitreous to reach the therapeutic site, avoid neutralisation by anti-bodies, traverse the inner limiting membrane and successfully deliver a transgene to the nucleus of the target cells.

These challenges can pose a barrier to successful development of ocular gene therapies. For example, while the Phase 1 trial of AAV2-sFLT01, a IVT delivered therapy for neovascular AMD originally under development by Sanofi Genzyme, showed a good safety profile at all doses,
development was halted by because of poor efficacy.

The work has been done designing vectors to improve performance in IVT delivered gene therapies, engineering vectors with enhanced immune resistance and membrane penetration, but the challenges are still significant, and to the author’s knowledge, there are no IVT therapies that can match the efficacy of SR or SC delivery.

Subretinal injection

Subretinal delivery is the gold standard for precision targeting of retinal cells using gene therapy. The technique is performed with a specialist cannula via a transscleral transvitreous chamber route or by passing a cannula through the suprachoroidal space, delivering a bolus between the neurosensory retina (NR) and the retinal pigment epithelium (RPE). The procedure must be performed in-theatre, requiring a vitrectomy prior to the injection, however it presents some distinct advantages over the less complex IVT. Direct injection to the retina provides a high drug load at the target site, ensuring high transduction efficiency and localised gene expression limited to the neighbourhood of the bolus and therefore, providing superb precision for targeted therapies.

Subretinal injection does however carry a higher risk of retinal detachment than other delivery techniques. Injecting a fluid bolus into delicate organic structures, subjects them to mechanical stress and this technique necessitates some degree of detachment between the NR and RPE. This separation is usually transient as the bolus is absorbed over time, but it still represents a real risk to patient vision. There are also logistical challenges with subretinal injection, since the surgical requirements for are resource-intensive and non-scalable.

Suprachoroidal injection

Suprachoroidal delivery presents a compromise between the procedurally simple but less efŠcacious IVT, and the more complex but targeted subretinal delivery. The key distinguishing feature of this approach is delivery of a bolus into the suprachoroidal space, a virtual space between the sclera and the choroid. Once inside the SC space, the therapy flows around the eye contacting anatomical structures adjacent to the choroid. The technique may be less invasive than IVT or subretinal delivery, while providing access to the deep structures of the eye and a broader distribution of therapy across those structures.

There is great potential in this approach, but the devices for consistent success are still relatively new, and it is still undergoing thorough investigation at clinical trial. Clinical data is still emerging, companies have paused suprachoroidal programs due to immune concerns. The route’s success will depend on reproducibility, safety and clinician familiarity.

Formulation and dosing strategies

All successful drug deliveries must consider technique, formulation and delivery device holistically and gene therapy is no different. Gene therapy formulations are complex. They must balance manufacturability, biological efficacy, stability for cold-chain storage and transport and deliverability for the chosen approach. Understanding how formulation rheology affects deliverability and dosing is essential. For example, viscous formulations are inappropriate for IVT since they slow diffusion and mixing in the vitreous, but viscous formulations are preferable for SC delivery as they offer better control over injectate spread in the SC space and are associated with lower interference with vision after the procedure.

Viruses and LNPs also require additional considerations by nature of their large size, relative to biologics and small molecules. These vectors require high multiplicity of infection to ensure transduction, which often necessitates bolus dosing, but high viral or LNP loads are more likely to induce an immune response. They are also shear sensitive and will degrade if subjected to excess stress, placing limits of formulation viscosity, injection rate and delivery time, all of which impacts patient experience.

Device design

The success of ocular gene therapy depends heavily on the devices used for delivery. Devices for IVT are conceptually simple, a syringe and narrow-gauge needle, typically 30G for injections of noncolloidal drugs or 27G for suspensions. There are also commercially available accessory devices to aid positioning, like the Precivia® from Veni Vidi Medical.

Subretinal injections require specialised devices consisting of cannulas sufficiently long to traverse the vitreous cavity or pass through the SC space and very narrow to limit procedural trauma, often 38G to 41G, with even narrower tips to aid retinal penetration. These cannulas are connected to a syringe or extension line for manual delivery or may be incorporated into a vitrectomy machine for automated pneumatic control. There is some overlap between devices for SR and SC delivery, like the Orbit® Subretinal Delivery System by Gyroscope Therapeutics, where ­exible cannulas can be deployed to traverse the SC space to puncture the retina from the rear side.

In principle, SC delivery devices may be similar to those used for IVT and common needle and syringe systems are still used. However, positioning a needle freehand accurately within a few tens of micrometres of a sensitive organ is a considerable challenge and requires highly trained clinicians to execute correctly. Catheter-based devices have been developed to address this like the Everads Therapy device. Advanced microneedle systems are also under development for SC delivery, like the Bella-Vue from Uneedle, which use very short narrow-gauge needles to control penetration depth through the sclera.

Many of these devices share similar challenges for gene therapy delivery, foremost of which is the requirement for accurate placement and drug spread. There is little distribution control during IVT delivery, but for SR and SC delivery, ensuring that the devices are suitable for the rheological characteristics of the therapy formulation is crucial for treatment.

Patient experience is central to the success of any therapy. Patients prefer low-risk, low-pain procedures, but are willing to accept more invasive methods if the vision outcomes are significantly better. The balance is between continuous but less invasive treatments, versus a single treatment that carries greater risk of complication but could provide enormous benefit across a patient’s expected lifetime. In either case, understanding of patient needs and timescales is critical.

Patient and clinician considerations

Clinicians, meanwhile, prefer well-understood procedures with low complication rates. IVT is widely accepted because of procedural simplicity, with expert clinicians able to perform multiple IVT injections per hour. SR and SC injections require additional training and confidence in the technology, and so device usability and reproducibility are key in bridging the gap towards adoption for these more advanced techniques.

Future directions for innovation

The future of ocular gene therapy lies in technological convergence. Artificial intelligence is already being used to design synthetic vectors with reduced immunogenicity. Non-viral delivery methods, such as optimised LNPs and naked DNA or RNA fragments, offer alternatives to traditional viral vectors. New AI, augmented reality, and virtual reality tools, like the EyeSi Simulator at the Royal College of Ophthalmologists in London, are also providing a platform for clinician training without the need for theatre time or expensive drug.

Inducible gene therapies, which allow for on/off control and dose modulation, are a similar exciting innovation, where the dose can be modulated with by excipients delivered systemically. This level of control may increase efficacy, reduce the rate of immunological adverse events and reduce long-term stress on retinal cells, while providing dose at a rate optimised for transduction efficiency. Such treatments are early in development and have not yet made the transition to ophthalmology, and also requires the patient to make additional clinic visits, which may dampen some of the benefits of ‘one-and-done’ treatments

Drug delivery is the linchpin of ocular gene therapy. The choice of route, formulation and delivery device determines not only the efficacy but also scalability, safety and patient experience. The techniques of IVT, SR delivery and SC delivery require differing devices, with the latter two more novel approaches also additional training and confidence from clinicians and hospitals for adoption. These challenges are not insurmountable, but device and therapy development demand a holistic approach. As ophthalmic gene therapy matures, collaboration between biotech innovators, clinicians, regulators and device manufacturers will be essential. The goal is not just to deliver gene therapy but to deliver clear vision, safely and effectively, to millions of patients worldwide.