In retinal degenerations multiple biochemical pathways and mechanisms within the photoreceptor cells and retinal pigment epithelial and overall visual cycle are affected. This complex pathophysiology poses many challenges but also presents possible targets for therapeutic intervention.

Until we understand the initial triggers of disease we can only ever treat its symptoms – Fighting Blindness funded researcher

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Neurodegeneration in the retina may be due to induced cell death triggered by a genetic mutation or as a result of oxidative stress in the cell. Whilst there are a wide range of factors that can initiate retinal degeneration, ultimately the end-point is the loss of photoreceptor cells that are required for vision.

Neuroprotective approaches aim to block cell death or strengthen pro-survival mechanisms and thereby protect visual function. For example, apoptosis is the term used to describe how cells decide to switch off and die. Apoptosis is a fundamental and essential process in the body.

However, sometimes apoptosis occurs abnormally, and in retinal degenerations it can lead to the death of the important photoreceptor cells that are required for light and vision. Scientists are currently investigating compounds for their “anti-apoptotic” properties that have the potential to protect or slow progression of sight loss conditions such as inherited retinal degenerations and Age-related macular degeneration (AMD).

Unlike gene replacement therapies, neuroprotective approaches do not depend on any specific mutation and therefore could be used to treat a number of retinal conditions. Neuroprotective strategies may also be used in conjunction with other interventions such as such as stem cell therapy and gene therapy, in the treatment of retinal diseases.

Many neuroprotective factors have been examined in the laboratory using animal or cell models. Neuroprotection is measured by the ability of compounds to slow or prevent retinal cell death. Another indication of neuroprotection by a compound is an increase in the release of other neuroprotective molecules in the cell.

A well-studied neuroprotective candidate is the growth factor cillary neurotrophic factor (CNTF). Growth factors are substances that promote the health and function of cells and tissues in the body. They are made by the body to sustain and repair itself and have important roles in cell survival. CNTF is a human growth factor that preferentially stimulates and protects human cells.

The neuroprotective effects of CNTF have been demonstrated in animal models of retinal degenerative diseases, with positive effects on cone and rod photoreceptor survival. CNTF is now being tested in clinical trial. The CNTF is delivered to the retina via a tiny implant containing retinal pigement epithelial cells, which release the growth factor into the eye. This technique is known as encapsulated cell therapy.

There has been some evidence, from high-resolution advanced retinal imaging, suggesting that CNTF promotes photoreceptor survival. This is a long term study and these patients will be monitored for a number of years to determine the efficacy of this treatment.

Another neuroprotective factor being explored is rod-derived cone viability factor (RdCVF). This has been identified in laboratory studies as a promising treatment candidate for Retinitis pigmentosa (RP) and other rod-cone dystrophies. It is believed that this factor protects cone cells from photo-oxidative damage.

Immune Regulation

Scientists are also investigating the involvement of oxidative stress and inflammation as a potential cause of disease and what part our immune system plays in disease progression. With this knowledge, they are looking at how to harness the healing power of the immune system to slow progression of vision loss in conditions like Age-related macular degeneration (AMD).

Management of Toxic Material

One of the characteristics of Stargardt disease is a vitamin-A recycling defect which can then lead to the build-up of waste products. Research suggests that the accumulated damage over time from toxins leads, ultimately, to loss of photoreceptors and vision.

Researchers are thereby exploring avenues which address the build-up of toxic material. Scientists in the US have developed a drug called ALK-001 by replacing hydrogen atoms in vitamin A with deuterium. Known as deuterated vitamin A, it “burns cleaner” than the natural form.

Deuterium is a safe, naturally occurring, non-radioactive form of hydrogen which is present in the human body. Promising animal studies showed that ALK-001 prevents the formation and accumulation of toxins, and vision loss in mice affected with Stargardt disease.

Building on this pre-clinical data, a four-week, Phase I safety-only study in people was successful; no adverse events, toxicity or side effects were reported. This intervention is a modified form of vitamin A, which, when metabolized in the retina, results in much less waste.

Following this, in 2015 the company Alkeus launched a multi-centre TEASE Phase II clinical trial recruiting 50 patients in 6 US sites for the drug ALK-001, which targets this waste-management problem ( Identifier: NCT02402660). Completion of the study is due end 2019.

Another drug in development works by slowing the build-up of toxic waste often associated with Stargardt disease. A Phase II clinical trial ( Identifier: NCT03033108) performed a safety analysis of this in the US. It was recently announced the company called Acucela are now advancing with a Phase 3 clinical trial.

Anti-vascular Agents

The most severe (wet) form of AMD is caused by the growth of abnormal blood vessels. These blood vessels damage the photoreceptor cells by invading the same space. In addition, the new blood vessels are leaky, so both blood and toxic products can leak out, also damaging the photoreceptor cells.

Blood vessels are stimulated to grow by a variety of factors, one of which is a protein called vascular endothelial growth factor (VEGF). This growth factor can be neutralised by injecting an antibody to it into the eye. Drugs like Lucenits®, Eyelea and Avastin® are antibodies that bind to VEGF. By doing so, the drug prevents it from stimulating the growth of new blood vessels. However, these antibodies must be injected directly into the eye on a regular basis.

Scientists are now exploring the potential of combination therapy. This means combining the anti-VEGF drug with another compound that targets another critical pathway associated with retinal degenerations. For example, by using an anti-PDGF (short for platelet derived growth factor). This can bind to cells on the outer lining of blood cells and has the potential to promote blood vessel regression and reduce scarring.

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