Eyeballing Advanced Medicine

Cell and gene therapies (CGTs) are among the most exciting therapeutic modalities pioneered in the last 30 years. They promise to treat a diverse range of intractable clinical indications and, when successful, deliver life-changing results. In 2017, Spark Therapeutics’ LUXTURNA product for Leber congenital amaurosis – a single-use AAV-based therapy that corrects a mutation in the RPE65 gene – became the first gene therapy approved by the FDA. Since then, a growing number of ophthalmic gene therapies have been tested in clinical trials to treat conditions such as age-related macular degeneration, Stargardt disease (an inherited form of macular degeneration), and choroideremia (a rare form of retinal degeneration).

Ophthalmic gene therapies are becoming popular within the CGT area, because the eye is an appealing target. It is an immune-privileged organ – thanks to the blood-ocular barrier – and involves compartmentalized anatomy that is easily accessible and can be examined in vivo by high-quality imaging techniques.  The eye can be used to test gene delivery to a wide range of tissues, as it contains endothelium (cornea), epithelium (cornea, ciliary body, iris), muscle (ciliary body), and neuronal cells (retina) while the presence of the blood-retinal and blood-aqueous barriers concentrates vectors in the target area, allowing therapies to be delivered with minimal systemic exposure. The use of the contralateral eye as a control is also beneficial. Furthermore, significant progress in understanding the pathogenesis of eye disease has afforded scientists an expansive knowledge of genetic mutations that cause vision loss. 

However, before any ophthalmic gene therapy can receive regulatory approval, it must overcome several challenges. Despite growing interest, it is predicted that only 30–60 gene therapies could be in active clinical use by 2030 (1). To successfully get more gene therapies to patients, it is essential to understand the hurdles so that we can implement solutions during the development process.

In truth, gene therapies are still an emerging therapeutic modality. As such, the gene therapy space lacks a foundation of approved products to leverage when developing new therapies. This means the regulatory framework is rapidly evolving, including the regulatory bodies’ guidance on safe market routes for gene therapies. Drug developers must therefore ensure they are familiar with and carefully follow the most current guidelines to avoid unnecessary delays during the preclinical development stage. For regulators, ophthalmic gene therapies also present unique safety considerations because they commonly involve a single dose. Such considerations include not only the accurate determination of the dose injection for first-in-human evaluation but also the extrapolation of in vivo immunogenicity into humans. Another significant challenge arises from the fact that ophthalmic gene therapies typically target rare genetic disorders, with drug developers often facing scarce patient populations and the resultant risk of underpowered clinical trials. With this in mind, developers must demonstrate the effectiveness of candidates for market application early on in preclinical testing.

So, in light of the above, what must organizations consider when designing preclinical ophthalmic gene therapy programs? First, because ocular anatomy varies widely between species, choosing models of the right species and at the right developmental stage is critical. On top of this, the selected in vivo model must accurately mimic the pathophysiology of ocular diseases in humans. Here, the identification and development of new models (e.g., to model de novo mutations) can help to better predict the efficacy of candidates in clinical studies. Specialized models, such as genetically modified mice, immunodeficient animals, and disease-induced models can also improve target validation of candidates, and thus should be explored. Pre-screening these models for ophthalmic abnormalities prior to preclinical in vivo studies is essential, as this can help ensure reliable modeling of disease states while reducing experimental variability. Once models are selected and studies have begun, leveraging advanced imaging technologies can allow researchers to precisely identify structural changes in the eye and thus evaluate the efficacy and toxicity associated to the gene therapy product in greater depth.

Developers must also bridge the gap between rodent disease models and human-relevant species (for example, pigs) to predict potential safety concerns for humans more effectively. For ophthalmic therapies in particular, the use of non-human primates may be required, as they have true macula (a section of retina at the back of the eye) and fovea (an area of the retina that allows for visual acuity) and the most similar retinal physiology to humans. 

Finally, for product approval, a validated in vitro potency assay needs to be developed – but all too often developers will consider this requirement far too late. To streamline your program, the development of this assay should start as soon as possible during preclinical testing, as not having a GMP-qualified in vitro potency assay during Phase III clinical trials will incur significant delays and sizeable costs. With ophthalmic gene therapies, the choice between ocular and non-ocular derived cell lines for in vitro potency assays and analytical release testing should be carefully considered, as non-ocular derived cells (adherent and growing in monolayers) may be easier to go through GMP qualification and validation as compared to retinal-based cell lines growing in suspension.

With more rigorous and optimized preclinical testing comes more robust evidence for clinical utility, avoiding unnecessary delays in (and increasing the likelihood of) regulatory approval by generating comprehensive data packages before Investigational New Drug application. Ultimately, these developments can help bring more life-changing therapies to patients quickly and allow the innovation happening in the ocular gene therapy space to continue at pace.