Professor Albert J. Augustin

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According to the clinicaltrials.gov database, there are around 2,000 gene therapies currently under investigation worldwide in many areas of medicine. In recent decades, the discipline has rapidly evolved.

Whilst the focus of most gene therapies has so far been on rare diseases, many additional drugs/products are currently being studied to treat disorders such as cancer as well as genetic and infectious diseases. And around 20 gene therapies are already available in the United States, having received Food and Drug Administration (FDA) approval.

The are several available approaches in gene therapy. We can replace a disease-causing gene with a healthy gene or deactivate a gene that is not functioning properly. In addition, a modified or completely new custom-designed gene can be introduced to treat a disease.

The basic principle is to target missing or faulty genes in monogenic diseases. Usually the “gene therapy drug” is given only once; it carries an instruction to change the sequence of one or more proteins. This change is necessary if those essential proteins are produced in a faulty manner: either they are not produced in sufficient quantities or the catalysis process controlled by the protein is not working correctly.

Major pathobiochemical or pathophysiological pathways have been investigated intensively. Gene therapy products include plasmid DNA and viral or bacterial vectors: in a subset of diseases, cells are extracted, genetically modified and then re-introduced into the body but more commonly a viral vector is used, which entails eliminating the virus gene and using its ability to penetrate the cell to safely deliver the new information.

From an immunological perspective, the eye is the ideal target for gene therapy, which thus makes it likely that, in the future, highly successful gene therapy approaches will lead to cures for certain diseases of the eye.

In 2017, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) became the first FDA-approved ocular gene therapy. Also approved in Europe (since 2018), it is used to treat certain inherited retinal diseases such as 

-related Leber congenital amaurosis or retinitis pigmentosa.

As mentioned already, gene therapies focus on monogenetic diseases. The approach becomes much more complicated for diseases with many pathways involved, such as age-related macular degeneration (AMD). Hence, current methods focus on gene augmentation and/or suppression to enhance or reduce the production of a molecule that plays a crucial role in the pathogenesis of the disease.

In wet AMD, this is vascular endothelial growth factor (VEGF). Its antibody (anti-VEGF) needs to be applied on a monthly basis, which may lead to both clinical and adherence problems. One way to overcome this is a surgical intervention such as the implantation of a slow-release device. An alternative would be the augmentation of anti-VEGF-production using a genetic approach.

One candidate that is currently being studied is RGX-314 (Regenxbio). This drug is delivered subretinally or suprachoroidally. It contains a novel adeno-associated viral vector (AAV8) and is currently in development for wet AMD, diabetic retinopathy and other retinal diseases.

As described above, the cells are transfected, which delivers the information to produce a protein. This protein is designed to neutralise VEGF and, by doing so, modify the pathway for the formation of new leaky blood vessels and retinal fluid accumulation.

Both approaches, subretinal and suprachoroidal, are surgically challenging. However, the suprachoroidal method, which our group used for the application of other drugs more than a decade ago, has been redesigned and appears to be a safe way to apply such a drug.

The positive interim results of two trials of RGX-314 (AAVIATE and ALTITUDE) using in-office suprachoroidal delivery were presented by Dr Robert L. Avery at the most recent meeting of the American Academy of Ophthalmology. The studies are including wet AMD and diabetic retinopathy patients without centre-involved diabetic macular oedema.

Another drug candidate in development is ADVM-022 (Adverum Biotechnologies), an adeno-associated virus vector encoding aflibercept. Results to date have shown that a single intravitreal administration of ADVM-022 is able to provide a safe and effective long-term treatment option for both wet AMD and diabetic macular oedema.

Looking at dry AMD, the approach is similar. Rather than focusing on genes that are responsible for the disease, we are trying to produce or antagonise factors that are part of the pathogenetic cascade. Inflammation has been shown to play a crucial role in the pathogenesis of dry AMD.

One way to tackle inflammation is by increasing the production of complement factor I (CFI), also known as C3b/C4b inactivator (a protein that regulates complement activation). Doing so has been shown to reduce complement activity and thereby inflammation.

About 3% of patients suffering from dry AMD have CFI mutations, with lower CFI levels giving a higher risk of dry AMD. GT005 (Gyroscope Therapeutics) is a AAV2 vector that delivers a plasmid construct expressing normal CFI; it is currently under investigation with promising results and no significant side effects so far, although the drug does need to be applied subretinally.

As described, clinical studies of promising ocular gene therapies are underway. However, safety remains a concern in this area of therapeutic medicine, where retinal pigment epithelium (RPE) changes and inflammatory reactions can take place. Thankfully, there have been some reports that these potential side-effects can be successfully controlled by topical steroids.

Until now only patients who have been heavily pre-treated have been included in trials. As well as the need to conduct intensive safety assessments, before these new gene therapy approaches can be used on regular basis in real-world settings, Phase 3 trials need to be completed and surgical procedures taught.

And so, while we are entering a new era of drug therapy, with gene therapy having the potential to change the way many diseases are treated (good news for our patients), there is still much work ahead. Both drug safety and drug delivery issues present major challenges that need to be addressed.

One promising future approach lies in the CRISPR-Cas9 gene-editing tool, which has recently been introduced for the treatment of a hereditary human disease. It functions rather like a molecular scissor to snip parts of the DNA: in this way, we can insert, delete or modify genes.

After identifying the defective genes, this exciting technology will provide the next step in gene therapy. We are already underway and have identified the defective genes in other hereditary diseases. Thus, this new technology will first be used in diseases with a clearly defined genetic signature.

Dr Augustin is professor of ophthalmology and chairman of the Department of Ophthalmology at the Karlsruhe Municipal Hospital, Germany. He has no financial disclosures related to this article.

Articles

Promising gene therapies in development are pinpointing steps in the pathogenic cascades involved in ocular diseases, such as VEGF for wet AMD and CFI for dry AMD.

Making strides in ophthalmology with modern gene therapy techniques 

Today, retina specialists have access to a broad range of imaging devices with different image-acquiring technologies. There has been rapid development in the field, from colour fundus photography, fluorescein angiography (FA), near-infrared (NIR) reflectance, fundus autofluorescence (FAF) and indocyanine green angiography (ICG) to high-resolution and swept-source optical coherence tomography (OCT), OCT-angiography (OCT-A) and adaptive optics.

The term ‘multimodal imaging’ is becoming increasingly used in the scientific literature to describe the approach to diagnose a single retinal disease by combining different imaging modalities. It can be defined as the use of more than one complementary technological system that is used to acquire images, concurrently or in a short period of time, for the purpose of diagnosis, prognostication, management and monitoring of disease.

Whilst the availability of today’s great number of imaging instruments is certainly impressive, it has the potential to cause the benefits of new diagnostic tests to be exaggerated, leading to premature adoption, unnecessary testing and increased health care costs. Thus, the question arises: which technologies are really necessary in clinical practice and which still need to be further evaluated?

Of the different imaging technologies, FA remains, at present, the gold standard technique for the evaluation, management and follow-up of patients affected by retinal vascular disease such as diabetic retinopathy and vein occlusions. And with its capability to identify choroidal vascular blood flow, ICG is helpful in detecting lesions underneath the retinal pigment epithelium, such as occult choroidal neovascularisations or polypoidal lesions. In addition, ICG plays a crucial role in the diagnosis of central serous chorioretinopahy.

Meanwhile, OCT is able to image retinal morphology and, specifically, retinal thickness, producing cross-sectional and three-dimensional images of the central retina. This technique is now well established in the diagnosis, management and treatment of almost all retinal diseases, mainly to quantify macular oedema and to highlight the signs of choroidal neovascularisation.

However, the scientific evaluation of additional parameters delivered by high-resolution OCT technology and a structure/function correlation is still needed. This is also true for adaptive optics, a technology that also provides a higher resolution by eliminating disruptive elements.

OCT-A represents the newest development in the field of retinal imaging. In combination with OCT, this non-invasive technique may show to be superior to conventional methods in the future. Numerous studies have been published surrounding its benefits in recent years, although no study has yet demonstrated the superiority of OCT-A over FA in both detecting and managing vascular diseases of the retina.

In real-world clinical practice, the use of OCT-A is challenging and we still need prospective data to show whether it can lead to better outcomes before we can use it in clinical practice. Until then, OCT-A will likely remain a scientific tool rather than become routinely used.

Another technique, FAF, can be used to observe both central and peripheral retinal health by evaluating the fluorescence of lipofuscin produced by photoreceptors. FAF also seems to be helpful in the diagnosis of hereditary diseases. However, its role in the diagnosis and follow up of dry age-related macular degeneration remains to be clarified, and a correlation between FAF and function is yet to be seen.

In summary, the spectrum of imaging technologies is rapidly evolving, providing fresh hope to ophthalmologists and their patients. However, all new technologies need to be critically evaluated before they transition from the bench to clinical routine practice, and we should be mindful of this as we look to embrace multimodal imaging.

Dr Emiliano Di Carlo
E-mail: emi.dicarlo@hotmail.it
Dr Di Carlo is an ophthalmology resident at University of Rome Tor Vergata, Rome, Italy.

Professor Albert J. Augustin
E-mail: albertjaugustin@googlemail.com
Prof. Augustin is professor and chairman of the Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany. He is a member of the Ophthalmology Times Europe Editorial Advisory Board.

Author | Professor Albert J. Augustin

Articles

Making strides in ophthalmology with modern gene therapy techniques

The emergence of multimodal imaging in ophthalmology