Gene Innovations

Research advances over the last two decades has transformed our knowledge of how the body works and the role our genes play in both its function and dysfunction. This increased knowledge has been greatly facilitated by the introduction of sophisticated laboratory techniques and an increase in cell and animal models of disease.

Much effort in this time has concentrated on finding the genes associated with genetic forms of sight loss; an area of research often called ‘gene mapping’ or ‘gene hunting’. As of January 2019, over 271 genes have been linked to inherited retinal degenerations (IRDs). As a result, gene-targeted innovations hold significant promise to treat genetic forms of sight loss.

However, variability in the underlying genetic problem can make targeting genes for therapy more difficult. With this in mind, researchers are examining various strategies to effectively (and accurately) replace, dampen down or silence the faulty genes associated with retinal conditions.

Retinal degenerations are ideal for gene therapy. Firstly the retina is easily accessible which allows for the delivery of potential therapeutics directly into it. It is also easily visualised which means that the effect of a treatment can be assessed. Thirdly, the eye as an organ, is largely protected from a systemic immune response, for example, following injection of a viral vector as described below.

Such has been the interest and marked potential in this area, clinical trials are now underway for many conditions including retinitis pigmentosa (RP), choroideremia, Leber hereditary optic neuropathy (LHON), Leber congenital amaurosis (LCA), Stargardt disease, achromatopsia, X-linked retinoschisis (XLRS) and age-related macular degeneration (AMD).

As of January 2019, there are over twenty gene therapies currently in phase I, II or III development. Techniques currently being investigated include gene suppression and replacement therapy, gene replacement/augmentation, gene editing, optogenetics and RNA therapies. For the most part, these strategies target one gene at a time.

However, in AMD for example, this condition is not associated with a single gene defect. Here, gene interventions are designed to produce proteins that block pathogenic pathways to inhibit angiogenesis (growth of new blood vessels) or cell death.

As research advances continue in the areas of genetic testing, diagnostics, patient selection, vector technology and surgical techniques, gene therapy holds great promise not only for treating genetic forms of retinal disease but also for protecting the retina from further degeneration. As such, it is important for individuals diagnosed with an IRD to be aware of the genetic mutation associated with their condition, as this will help determine if there is a treatment or clinical trial available which may be suitable for them.

The Target 5000 programme offers free genetic testing for people living in Ireland with an IRD. For further information, please contact the Research department on 01 6789004 or

In this section

Gene Replacement

Gene Replacement therapy (also known as gene corrective therapy or gene augmentation therapy) is designed to treat inherited retinal degenerations caused by a single recessive or X-linked gene mutation (misspelling in one gene). It works by adding a normal and healthy copy of the gene into they eye, which then enters the cells that need it to produce a protein correctly.

To insert a gene into the cell requires a specific delivery strategy. One way to deliver a functional gene to the cells is by using a viral vector. Vectors can be described as chaperones that carry the non-harmful virus containing the correct and desired gene into the eye.

Vectors can be compared to a taxi cab delivering its’ passenger (in this case a gene) to its’ final destination (in this case the retinal cell). These viral vectors can be delivered into the subretinal space of the retina or, in some cases, injected into the vitreous cavity of the eye.

Once delivered, the newly inserted gene can now function as a normal gene would, allowing proteins to be made and the cell to function normally. It is important to note, that for this form of treatment to work, the presence of viable retinal cells at the back of the eye is required.

There are a number of gene augmentation/replacement therapies in clinical trials targeting some of the following genes: RPE65 in Retinitis pigmentosa (RP) and Leber congenital amaurosis, CHM in Choroideremia, CNGB3 and CNGA3 in Achromatopsia, RS1 in X-linked Retinoschisis, MY07A in Usher syndrome, ABCA4 in Stargadt disease and ND4 in Leber hereditary optic neuropathy (LHON).

A Gene Therapy in Practice

The development of new and more optimised vector delivery methods is an on-going area of investigation for scientists. Clinical trials have shown that there is no substantial immune reactivity or systemic adverse events associated with treatment with adeno-associated virus (AAV) and lentivirus vectors.

In 2018, positive safety and efficacy results in clinical trials led to successful regulatory approval for the very first gene therapy for a genetic disease, Luxturna™. This is the first gene therapy approved for a genetic retinal condition. This creates cause for optimism as this same method is being used to target other genetic retinal disorders.

Luxturna™ has been approved to treat patients with a confirmed biallelic RPE65 mutation-associated retinal dystrophy. The term biallelic means that the individual carries a mutation in both copies of the RPE65 gene (a paternal and a maternal mutation). These individuals experience progressive deterioration of vision over time.

This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness. The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision. Mutations in the RPE65 gene leads to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision.

Luxturna™ works by delivering a normal copy of the RPE65 gene directly to retinal cells. For patients to benefit from the therapy, they must also have enough remaining cells in the retina (the thin layer of tissue in the back of the eyes) as determined by a healthcare professional.

These retinal cells then produce the normal protein that converts light to an electrical signal in the retina, thereby stopping further vision loss and restoring some functional vision. Luxturna™ uses a naturally occurring adeno-associated virus (which has been modified and rendered harmless) as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision.

To learn more about gene augmentation please contact the Research department on 01 6789004 or

Gene Suppression and Replacement

Genetics can be incredibly complex. In types of autosomal dominant forms of sight loss, the faulty gene can inhibit or block the function of the remaining normal copy of the gene. This is called a ‘dominant-negative’ effect.

The faulty copy of the gene may also fail to produce a functional protein and the remaining normal copy of the gene is insufficient to provide for the normal needs of the retinal cells (‘haploinsufficiency’). In these cases, gene replacement therapy will not be sufficient to restore vision and scientists have been investigating alternative strategies.

For example, to address a ‘dominant-negative’ effect, the faulty copy of the gene needs to be ‘switched off’ so that it can no longer harm the retinal cells or prevent the other normal gene from functioning.

Gene suppression and replacement therapy has been developed as a technique which aims to target the gene, regardless of the mutations which may affect it (mutation-independent). As the name suggests, this therapy performs two important roles. The first is to suppress the gene carrying the mutation (both copies of the gene need to be suppressed; one copy inherited from a person’s mother and the other from their father). The second is to replace this mutated gene with a normal/healthy gene to restore the normal function.

Supported by Fighting Blindness, this technique was examined in animal models by a group in Trinity College Dublin, developing a potential gene therapy called RhoNova™. This intervention specifically focused on the Rhodopsin gene associated with autosomal dominant Retinitis pigmentosa (adRP). In fact, there are over 150 mutations within the Rhodopsin (RHO) gene associated with this condition.

Therefore, this dual vector gene therapy was designed to suppress the expression of the faulty rhodopsin gene and deliver a normal, healthy rhodopsin gene as a replacement. Similar translational research studies have also taken place by scientists at the University of Pennsylvania (Penn) and University of Florida.

In 2018, their work showed that a single-gene therapy vector that combines knockdown (dampening) of the causative gene with its replacement by a resistant wild-type copy can prevent photoreceptor cell death and vision loss in a naturally occurring canine model of the disease.

To learn more about gene suppression and replacement therapy, please contact the Research department on 01 6789004 or

Gene Editing

Recent revolutions in science have yielded major breakthroughs in genetic engineering, one of those being gene editing. Where traditional research initiatives sought to correct for a damaged or non-functioning gene by inserting a normal gene, researchers have encountered difficulties in delivering genes which are too large for vectors (delivery vehicles).

Examples include the ABCA4 gene associated with Stargardt disease . Gene editing effectively bypasses these challenges and seeks to edit the damaged or non-functioning gene directly.

CRISPR-Cas9 is a recently developed gene editing technique. However, it has quickly been heralded as a significant step forward in gene innovation as it allows for the quick, easy and precise editing of DNA. As the name suggests, this system has two major components, one piece which targets the gene and another which cuts it for repair.

CRISPR comprises a specific sequence of RNA (an exact template of DNA, which forms the instructions to make proteins in human cells) which seeks out the gene containing the DNA which is mutated. The Cas9 element is an enzyme which acts as the molecular scissors, cutting out the non-functioning gene. From there, researchers can prompt gene repair by using the cell’s own DNA repair system or by providing a more specific replacement.

Despite the exciting advances being made using gene editing, this technology is still in development and further work is needed to fully test this approach in humans. Caution must be advised until it is fully evaluated and validated for use in the clinic. At this point, careful thought must be given to ethical concerns, for example when and in which cells should gene editing occur.

Consideration must also be given regarding permanent changes to human DNA. The prospect of being able to precisely target disease-causing genes is promising, but the scientific and patient community must agree to air on the side of caution until decisions are made about its safe and acceptable use.

To learn more about gene editing, please contact the Research department on 01 6789004 or


The term ‘optogenetics’ is derived from the Greek work for visible or seen. Starting out in the neuroscience field, optogenetics is a neuromodulation technique used for the study of neural circuits in the brain. It uses a combination of techniques from optics and genetics to control and monitor the activity of individual neurons (nerve cells) in living tissue. Optogenetic therapy is a way of potentially restoring vision by targeting specific cell types in the retina with ‘optogenes’ that enable the cells to become light sensitive.

Light-sensitive rod and cone photoreceptor cells are essential for vision because of their ability to convert light into visual information. Both react to incoming photons by generating an electrical signal. Another type of retinal nerve cell called a ganglion cell then collects this information and fine tunes it before it is sent to the brain where it is interpreted as vision.

The loss of rod and cone photoreceptors is at the root of many sight loss conditions including inherited retinal degenerations such as Retinitis pigmentosa (RP). Many research teams around the world are now exploring ways in which they can replace, support or bypass these damaged photoreceptors.

By taking advantage of nature’s ability to respond to light, optogenetics is an exciting and innovative technique that has the potential to stimulate an alternative route to vision in the absence of working rod and cone photoreceptors.

How does optogenetics work?

Algae found in ponds and lakes contain light sensitive proteins called rhodopsins. These rhodopsins become active when exposed to light. For example, when a nerve cell containing rhodopsins is exposed to a certain colour of light, the rhodopsins becomes stimulated and change shape which in turn changes the activity of the nerve cell.

In many retinal degenerations, ganglion cells survive long after the light-sensitive rods and cones are gone, making them a prime target for vision restoration.

However, scientists have shown that by inserting rhodopsins found in algae into ganglion cells, they can empower these retinal nerve cells to respond to light. This brings considerable potential for providing a new type of cell in the retina which can detect light and then communicate that information to the visual part of your brain.

Therefore, when your eye receives light from the environment, it is anticipated that the retinal ganglion cells will be directly stimulated and send signals along your optic nerve to your brain without any input needed from other parts of your retina. This is achieved through a single injection of harmless viruses laden with algae DNA into the centre of the eye. A requirement is the presence of some retinal cells types in the retina such as bipolar or ganglion cells, which can be targeted by optogenes.

Scientists are currently working to understand how optogenetics can restore sight to individuals with retinal diseases. To date, these methods have been shown to bring back rudimentary vision in animal models. Such positive results have prompted examinations in humans and more than two early clinical trials are currently underway to evaluate if optogenetics can restore sight to people living with advanced RP. In most trials, investigators are combining the gene therapy with an external visual stimulation assistive device (goggles).

The future for optogenetics

Optogenetic therapy does not rely on specific genetic mutations and therefore could be used to treat a wide variety of inherited retinal degenerations. Current clinical trials are focusing on RP, but if successful, this gene therapy may also hold potential for other conditions including Age related macular degeneration (AMD) in the future.

This is a revolutionary and fast moving technology which will be closely examined by many to establish, how safe and effective the potential treatment is. The light sensitive proteins inserted into the cells can only respond to certain coloured light in the environment and time will tell how humans will respond to this light and how it is processed in the brain.

The outcome of this potential therapy will depend on many factors such as the degenerative state of the retina, the ability of the patient to learn the new retinal language driven by the optogene and the rehabilitation programme provided. Overall, there is the challenge to try to restore as much of the normal vision as possible.

In designing such a system, there is a necessary balance between a system that has high light sensitivity, such that goggles are not necessary, one that can respond over a broad range of intensities, and one that has response speed adequate for motion vision.

To learn more about optogenetics, please contact the Research department on 01 6789004 or

RNA Strategies

This is an emerging strategy being investigated for eye conditions. Most people have heard of DNA but the important role of RNA is often less understood. DNA contains genes, which are the instructions on how to make the functional building blocks of the cell, such as proteins which are important for structure and function in the eye.

However to get from the DNA to protein, the information in the DNA is first copied into RNA. The RNA acts as the “blueprint” for making proteins. Genetic diseases are caused by mistakes, or mutations, in the DNA. These mutations are copied into the RNA blueprint, which means the protein is also not made correctly.

RNA therapies are short pieces of RNA made in a laboratory and aims to repair the RNA blueprint so that the protein is made correctly. While gene therapies as we know them target DNA, this approach also addresses the underlying cause of the disease but without making permanent changes to the DNA. RNA therapies can be designed to be administered directly as intravitreal injections into the eye.

Researchers are developing antisense oligonucleotides to target RNA. These are synthetic (man-made) drugs which can encourage the cell to ‘skip’ the part of the RNA that contains the mutation so that the remaining RNA can still make the protein.

The protein will be slightly shorter than normal, but is expected to still perform its function. Clinical trials are now investigating the potential for this type of intervention for certain forms of Leber congenital amaurosis (CEP290 gene) and Usher syndrome (USH2A gene), with progress on-going.

Another area of investigation involves RNA interference (also known as gene silencing). There are instances where it is not desirable for RNA to provide instructions for protein development, especially if the protein has a harmful effect or plays a harmful role, such as in eye inflammation for example.

Researchers have previously examined RNA interference (RNAi) agents, which specifically target particular pieces of RNA, in animal models of Diabetic retinopathy and Uveitis, with some positive results. Further work is needed to develop RNAi agents as an effective therapy for eye conditions.

To learn more about RNA strategies please contact the Research department on 01 6789004 or

Other Gene Strategies

Other therapeutic strategies being explored include those which aim to minimise environmental or genetic insults in the retina. For example, by using non-harmful AAV or lenti-viruses, the delivery of decoy receptors or anti-angiogenic genes into the eye may halt or prevent neovascular complications in Wet Age-related macular degenerations (wet-AMD).

Epigenetics is another emerging area of focus for scientists in the laboratory. Epigenetics is the study of biological mechanisms that will switch genes on and off, otherwise known as gene expression.

While traditional genetics describes the way the DNA sequences in our genes are passed from one generation to the next, epigenetics describes passing on the way the genes are used. Increased understanding of this phenomenon in relation to retinal degenerations may guide therapeutic approaches in the future.

To learn more about gene therapies, please contact or ring 01 6789004.

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