The number of effective cell and gene therapies is growing rapidly, especially for the treatment of ocular diseases. In the near future, they promise a one-time treatment for inherited retinal diseases (IRD), age-related macular degeneration (AMD) and a range of other disorders. Once achieved, this will be a gamechanger – transforming the lives of patients who currently face monthly injections and the fear of undertreatment or even blindness if their schedule is not maintained.
Intraocular lens delivery to the eye: the next frontier for innovation
In our recent report “Towards 2040 – A vision for the future of ophthalmology” we highlighted the need to reduce workloads and increase patient access if we are to cope with the overwhelming eye care demands in the next 20 years. Gene therapies promise to cut eye disease at its source, preventing rather than fixing vision problems. The challenges are enormous, but the reward is equally large.
Gene therapy, then, represents an exciting prospect. And not surprisingly, plenty of debate has surrounded this cutting-edge approach to treatment, and the benefits that will flow from it. Less attention has been focused on the critical issue of delivery to the eye. Effective innovation here is pivotal to the success or failure of the new treatments. So, let’s put that right and throw the spotlight on ocular gene therapy delivery methods.
Like all treatment options, gene therapy carries unique challenges and risks. Chief among them is that most of the approaches of this type currently in development demand much more precise and targeted injections than are used elsewhere. This highlights our key point – significant innovation is needed to help surgeons safely and effectively deliver these remarkable solutions.
In an earlier article in our eye delivery series, our colleague Tim Phillips described intraocular lens delivery as ‘the next frontier’ for innovation. In our opinion, gene therapy injection advances are just as crucial. So, this time, we are going to explore the pros and cons of the various injection pathways and methods being developed for these revolutionary therapies.
Gene therapy, why the eye?
First, a word about gene therapy itself. It’s based on an understanding that each person's distinctive genetic profile makes them vulnerable to specific diseases. With gene therapy, the idea is to modify the genetic information within the specific cells of the patient that are responsible for a disease, and transform them into healthy, stable cells.
Early trials of these therapies showed significant immune response issues. Since the early 2000s, a great deal has been achieved in the areas of vector dynamics and safety. Vectors are the vehicles that ferry the desired DNA into the host cell. The most common is a class of vectors called adeno-associated viruses or AAVs, which promise minimal immune response risks.
Disorders within the eye were the focal point of many of the initial gene therapies because, among other reasons, the eye is a closed system with specific immune privilege. This means that the eye limits local immune and inflammatory responses. Additionally, the eye is home to a collection of specific, genetic mutations which can be targeted for gene therapy. The first, and so far, only of these therapies approved by the FDA is Luxturna from Spark Therapeutics, which is used to treat inherited retinal dystrophy, a rare genetic disorder.
Ocular gene therapy delivery methods
Right now, there are four primary gene therapy injection pathways to consider. Subretinal, intravitreal, suprachoroidal and suprachoroidal pathway to subretinal. While only the first has been given FDA approval, the other three are quickly working toward acceptance. Assuming they all get perfected enough for safe and effective delivery, each will have benefits and drawbacks.
The biggest difference between these options is whether they require a vitrectomy – where the vitreous humor gel that fills the eye is taken out and temporarily replaced to offer better visual and mechanical access to the retinal surface. When this procedure is required, the surgery needs to be conducted in an operating room (OR) with vitrectomy equipment. The FDA approved method (for Luxturna) is a subretinal injection and therefore requires a vitrectomy.
The other three methods, still in development, offer the promise of procedures without vitrectomies and which can be carried out within a doctor's office or clinic instead of an OR. It’s likely that these would be simpler, faster and less costly.
Key questions, though, remain about these non-vitrectomy injection pathways. For instance, will they:
- Offer the same level of efficacy? (Preferred)
- Increase the immune response reaction? (Problematic)
- Raise interocular pressure (IOP)? (Problematic)
Let’s go a bit deeper on each pathway to better understand the motivations and challenges.
We’ll begin with the vitrectomy. In figure 1 you can see the activities leading up to the subretinal injection itself. Most of these steps will be required for any of the injection systems or pathway. The biggest difference is the pre-injection quadrant. The vitrectomy requires special equipment and the use of the OR – it is also a procedure that requires the careful interplay between several healthcare professionals (HCPs). On the plus side it is a very refined process, done with proven equipment, and performed safely many times a day throughout the world.
With three trocars (ports) inserted into the patient's eye, and after the vitrectomy is performed, the surgeon looks through a microscope into the back of the eye (the retinal surface). He or she simultaneously inserts a needle through one of the three ports and holds a light source through another. The control over that needle must be very, very precise as the needle approaches the retina. The target is a theoretical space between the back of the retina and the surface of the choroid. It is theoretical because there will be no space there until the solution (a mixture of the vector and the diluent) can be injected to create the space by pushing the two surfaces apart. (See figure 2.)
Subretinal challenges and benefits
Subretinal delivery is a tricky and micro-precise process that demands a great deal of training if it is to be performed successfully. One issue is that no two doctors do it exactly the same way. There is very little physical feedback against the tip of the needle as layers of the eye are penetrated, so the doctor cannot actually feel layers – the feedback is almost entirely visual, which is not perfect. There are other aspects that make this trickier than the other options. Suffice to say the level of surgical skill required is quite high. On the plus side, subretinal injection does work well. While not simple, a successful injection delivers the therapy to the exact location where it is needed, and without an increase in interocular pressure or a heightened immune response risk. And let’s not forget it is the only pathway approved so far.
In another earlier article, Suresh Gupta detailed the evolution of intravitreal drug delivery. This is an option being given a great deal of attention for gene and cell therapy as well. As Suresh described, it is a mature injection method compared to the more adolescent subretinal injection process outlined above. (See figure 3.)
Intravitreal benefits and challenges
There is no vitrectomy required – which means this can happen in the clinic or doctor’s office without much of the pre-injection complexity and anxiety producing precision of subretinal procedures. The doctor still needs to be trained and careful, but it is a quick and simple procedure in comparison.
On the other side of the coin, there are several impediments to success for intravitreal gene therapies.
- When injected into the relatively vast vitreous humor the vector is diluted before getting to the target cells
- When injected into the vitreous, the vector is unprotected from the host’s immune response which further diffuses the therapy
- It is challenging to get through the ILM (internal limiting membrane), a robust boundary between the vitreous and the retina
Pharma and device companies are working hard to overcome these, and other, obstacles because the upsides for market acceptance and human factors are abundant. One area of investigation is in identifying mutant AAV vectors that could increase penetration through the IML.
Like intravitreal injections, suprachoroidal injections are relatively straightforward and could be carried out in an outpatient setting. With this method, therapies can be delivered to the retina by injecting them, using microneedles matching the thickness of the sclera, into the potential suprachoroidal space. (See figure 4.) An injection delivered here can flow around the entire circumference of the eye and the vectors are also able to traverse through the surface of the RPE and to the target photoreceptors. It appears that this method can match the efficacy of the subretinal injection.
It is early days, and there are some clear challenges. Testing is showing inconsistency in effectiveness between different AAV vectors, while the triggering of host immune responses is also a concern. As promising as the initial findings have been, there is still a lot of work to do.
Suprachoroidal pathway to subretinal injection
The final pathway shares the same promise of in-office or in-clinic injection as the intravitreal and suprachoroidal methods. Instead of being a direct injection into the suprachoroidal space, this method uses that potential space as a pathway to get behind the eye and inject directly into the subretinal space from the opposite side. This avoids the vitrectomy and avoids puncturing the surface of the retina. The procedure is more involved than both the intravitreal and the suprachoroidal injections but can be far more targeted.
In this method (Orbit SDS, Gyroscope Therapeutics) a small flattened, bendable canula is inserted through a slot in the surface of the eye and travels along its circumference between the sclera and the choroid until it reaches the injection location. It can then deploy a microneedle at a shallow angle through the choroid, delivering the vector (forming a bleb) between the choroid and the retina. (See Figure 5.)
This novel pathway is still in preclinical stages and the challenges are less well documented. It seems, though, that there is potential for postoperative pain and inflammation due to added tissue disruption.
Matching therapies and delivery system
So, to recap, ocular gene therapies are on the frontline for treatment of IRD’s as well as some more common conditions, like AMD. Today, the only approved path for administering ocular gene therapies is a subretinal injection in an OR, incorporating a vitrectomy. But the promise of simpler, safer and more cost-effective delivery methods is being realized quickly. With the promise of more and more gene therapies being developed so are new systems to improve the usability of the approaches described above. This span a wide spectrum from micro-dosing subretinal delivery systems to surgical robotic approaches.
Each of these delivery systems, including subretinal, will continue to be refined. Newer generations of vectors will improve in performance and capacity. Immune responses will be lowered, and desired mutations will be more impactful. The choices for vectors and delivery pathways will depend on the disorder, the cell type and the specific location of the effected ocular tissue. Matching the new therapies with the right delivery system will depend on a variety of factors. For instance, gene therapies for IRDs may require highly accurate vector delivery leveraging a subretinal injection, while less targeted approaches could benefit from a less invasive pathway like intravitreal. A great deal will be learned about these innovative delivery methods as clinical trials progress, but one thing is for sure, we can see a future of ocular gene therapy with many delivery pathways to success. Why not drop me a line if you’d like to pick up on any of the points made in my article. It would be great to continue the conversation.
Authors: Gregg Draudt and Luis Diaz-Santana