Available treatments for IRDs

The development of effective therapies to prevent, cure or slow the rate of disease progression of inherited retinal disorders (IRDs) has been limited to date. However, recent progress in identifying the gene-causing mutations and characterising the disease mechanisms has provided opportunities for development of new therapeutic approaches.

At the current time, there are few approved and available treatments for people with IRDs. These currently consist of a visual prosthetic device (Argus® II Retinal Prosthesis System), and a gene therapy treatment (Luxturna) that was approved by the FDA in the United States in December 2017 and by the EMA in Europe in November 2018, for treatment of patients with IRDs caused by mutations in the RPE65 gene.

Argus® II Retinal Prosthesis System

The Argus® II Retinal Prosthesis System (“Argus II”; Second Sight Medical Products, Inc., CA, USA) is a retinal implant (artificial retina) designed to provide artificial vision to patients with near total vision loss due to outer retinal degenerative diseases, such as retinitis pigmentosa (RP). Argus II received CE-mark approval for commercial use in Europe in 2011, and Food and Drugs Administration approval in 2013 to treat adult patients with advanced retinitis pigmentosa in the United States. To date, Argus II been used by almost 300 people worldwide.

Argus II consists of a miniature video camera mounted on a pair of eye glasses. The video is sent to a small patient-worn computer containing a video-processing unit (VPU), where it is processed and transformed into instructions then sent back to the glasses via a cable. These instructions are transmitted wirelessly to an electrode array on the retinal implant on the surface of the retina, which emits small pulses of electricity. These electrical pulses bypass the damaged photoreceptors and stimulate the retina’s remaining cells, which transmit the visual information along the optic nerve to the brain. This process creates the perception of patterns of light which patients can learn to interpret as visual patterns.

Components of the Argus® II Retinal Prosthesis System

In clinical studies, Argus II has demonstrated improvements in visual function and performance on orientation and mobility tasks. Post-marketing studies to further evaluate its long-term safety and effectiveness are currently underway in Europe and the United States.

The Implant
External Equipment

Image credit: Second Sight

Luxturna (voretigene neparvovec)
gene therapy

In December 2017, the first commercialized gene therapy for the treatment of an inherited retinal disease, voretigene neparvovec (tradename: Luxturna, Spark Therapeutics), received approval from the United States Food and Drugs Administration (FDA) in December 2017. In November 2018, the European Medicines Agency (EMA) approved Luxturna for marketing authorisation in the EU. This authorisation is valid in all 28 member states of the EU as well as Iceland, Liechtenstein and Norway. Luxturna is approved for use in children and adults who have vision loss due to inherited retinal diseases caused by mutations in both copies (bialleic) of the RPE65 gene and have sufficient viable retinal cells.

The RPE65 gene provides instructions for making a protein that is essential for normal vision function. The RPE65 protein is involved in a multi-step process called the visual cycle, which converts light entering the eye into electrical signals that are transmitted to the brain.

Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. People with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. Mutations in the RPE65 gene account for approximately 2% of cases of recessive RP and between 6 to 16% cases of Leber congenital amaurosis (LCA).

Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal RPE65 protein that converts light to an electrical signal in the retina to restore patient’s vision loss.

Luxturna is administered via subretinal injection in both eyes separately and on separate days. This procedure performed is a specialist eye surgeon. It is given as a one-time treatment.

The approval of Luxturna in the United States was based on the results of a clinical trial programme that enrolled a total 41 people between the ages of 4 and 44 years, all of whom had had confirmed biallelic RPE65 mutations. The effectiveness (efficacy) of the Luxturna was demonstrated by a Phase 3 clinical trial that enrolled 31 participants. The study found that at 1 year after the treatment, participants who received Luxturna had significantly improved light sensitivity, visual fields, and navigational ability under dim lighting conditions, compared with the control group (participants who were not treated Luxturna). In addition, no serious Luxturna-related adverse events were observed among individuals treated with Luxturna during the study.

In the United States, the manufacturers (Spark Therapeutics) have priced Luxturna at approximately $425,000 per one-off treatment (~$850,000 if a patient has the procedure on both eyes). They have also agreed an outcomes-based rebate arrangement with some healthcare insurers whereby the company will pay rebates if patient outcomes fail to meet a specified threshold, linking the payment for Luxturna to both short-term efficacy (30-90 days) and longer-term durability (30 months).

Please refer to our Advocacy section for information/tools on how to advocate for new, higher-cost therapies.

Advocacy

Investigational Therapies for IRDs

Gene Therapy

Identification of the specific gene mutations that cause IRDs has provided the opportunity to develop novel therapies targeted towards addressing the genetic defect. One of the most promising therapeutic approaches that is being evaluated in clinical trials of people with IRDs is gene therapy.

In gene therapy, genetic material is inserted into cells to compensate for abnormal genes or to make a beneficial protein in order to treat a disease. The most common type of gene therapy being investigated for the treatment of IRDs in clinical trials is gene augmentation therapy. Many IRDs are caused by specific gene mutations which lead to reduced production or loss of the function to the proteins they make (so-called “loss-of-function” mutations). With gene augmentation therapy, a normal functioning version of the disease-causing gene is inserted into the affected retinal cells helping them to produce sufficient levels of the protein, restoring its normal function and preventing cell death.

The potential of gene augmentation therapy for the treatment of IRDs is highlighted by the recent approval, by the FDA in the United States and the EMA of the EU, of voretigene neparvovec (tradename: Luxturna). Luxuturna is approved for the treatment of the RPE65 mutation-associated inherited retinal disease, LCA – click here for further details about Luxturna

Other forms of gene therapy being evaluated as potential treatment options for IRDs include “gene inactivation” – this approach involves blocking the expression of genes with “gain-of-function” mutations that result in the production of harmful proteins that cause retinal degeneration.

The use of new “gene-editing” technologies such as CRISPR-cas9, which can be used to directly repair disease-causing mutations within the affected retinal cells, is another experimental approach that could potentially applied to the treatment of IRDs in the future.

Numerous clinical trials are currently evaluating the safety and effectiveness of gene therapy in several IRDs, including LCA, X-linked juvenile retinoschisis, RP, choroideremia, achromatopsia, and Leber Hereditary Optic Neuropathy. You can find a list of current trials related to IRDs here. You can also find trials by searching on the website that lists most clinical trials, however it must be noted that not all trials listed on the clinicaltrials.gov website are valid or vetted, and so we always advise that you talk with your ophthamologist about possible clinical trials participation.

Regenerative stem cell therapy

IRDs are characterised by the irreversible loss of retinal cells, including retinal pigment epithelium (RPE) and photoreceptor cells (rods or cones), which leads to vision loss.

Stem cells are undifferentiated immature cells that are capable of self-renewal and can differentiate into specialist cell types, including RPE and photoreceptor cells. The application of stem cells to replace or repair damaged cells in the diseased retina, potentially restoring visual function, is an important area of ongoing research IRD drug development.

There are different types of stem cells that are being evaluated as potential treatment of IRDs (summarized below):

  • Human embryonic stem cells (hESCs): these are stem cells cultivated from the inner cell mass of the embryo (blastocysts) during the early stages of embryonic development. hESCs are known as “pluripotent” stem cells because they have the ability to differentiate into almost any cell of the body
  • Adult stem cells: also known as somatic or mesenchymal stem cells (MSCs), these stem cells are isolated from adult tissues, such as the bone marrow, muscle, or fat (adipose) tissue. They are capable of differentiating into the adult cells of the tissue they are harvested from. Experiments have shown that stem cells derived from bone marrow may be able to rescue and repair existing damaged retina by releasing proteins that help promote the growth and survival of retinal cells.
  • Induced-Pluripotent Stem Cells (iPSCs): are a sub-type of pluripotent stem cells that originate from differentiated adult cells, such as skin cells or blood cells. The adult cells are genetically re-programmed to gain the pluripotent properties of embryonic stem cells, and can then be differentiated into specific cell types, including RPE or photoreceptor cells.
  • Progenitor cells: are similar to stem cells but are more specific because they are already programmed to differentiate into their “target” cell types (e.g. RPE or photoreceptor cells)

Currently, there are no approved stem/progenitor cell-based therapies available for the treatment of IRDs, although several clinical studies are evaluating the effectiveness and safety of this approach.

It is important to caution that, in the past few years, there have been reports from the United States of patients developing severe vision loss after receiving adipose tissue-derived “stem cell” therapies at unregulated clinics. In these cases, the interventions given had not undergone testing in formal clinical trials to evaluate their safety and effectiveness. It is imperative to consult your own health care provider before investigating or undertaking any interventions.

Neuroprotective Agents

Several therapies that may slow the photorececeptor degeneration in patients with IRDs have been evaluated, or are currently being tested in clinical studies:

  • Valproic acid: a clinical trial found no benefit for orally administered valproic acid, compared with placebo (a dummy treatment) for the treatment of autosomal dominant RP.
  • Vitamin A and fish oil supplements (docosahexaenoic acid [DHA]): data from clinical trials have shown only a modest reduction in the rate of retinitis pigmentosa disease progression in patients who had taken a combination of Vitamin A and DHA
  • N-acetylcysteine (NAC): A Phase I clinical trial (FIGHT-RP1 Study; NCT03063021) is evaluating the safety and tolerability of oral NAC in patients with retinitis pigmentosa. This study was initiated based on the observation from preclinical studies that oxidative stress is associated with damage to photoreceptors (cones), and NAC has been shown to prevent retinal degeneration in preclinical studies
  • Ciliary neurotrophic factor therapy (CNTF): In preclinical models, CNTF was found to slow photoreceptor degeneration, but demonstrated no benefit in a randomized clinical trial conducted in patients with early or late-stage retinitis pigmentosa.
Visual Prosthetics

A visual prosthesis, sometimes referred to as a “bionic eye”, is a device designed to restore visual function to a person with partial or total vision loss. In the past few years, several visual prostheses have been developed for use in people with IRDs. Details of some of these are summarized below:

Argus® II Retinal Prosthesis System

This first prosthesis on the market was the Argus® II Retinal Prosthesis System (“Argus II”; Second Sight Medical Products, Inc.). Argus II uses an epi-retinal implant that is surgically inserted on surface of the retina to provide artificial vision to patients with outer retinal degenerative disease such as retinitis pigmentosa. It received CE mark for commercial use in Europe in 2011, and FDA approval in 2013 for the treatment of adult patients with advanced RP. To date, Argus II been used by almost 300 people worldwide.

In clinical studies, Argus II has demonstrated improvements in visual function and performance on orientation and mobility tasks. Further post-marketing studies to evaluate its effectiveness and safety are currently ongoing in Europe and the United States.

The Argus II Implant

Argus II: External equipment

IRIS®II Bionic Vision System components

Image credit: Second Sight

Other retinal prostheses under development or being evaluated in clinical studies include:

IRIS®II bionic vision system

The Intelligent Retinal Implant System (IRIS®) II bionic vision system (Pixium Vision, Paris, France) was awarded the CE mark approval  in mid-2016 to market the product in Europe for people with vision loss from outer retinal degeneration. Reimbursement negotiations are currently underway with health authorities in France and Germany.

The IRIS® II system consists of a mini camera housed in a pair of glasses, which is intended to mimic the actions of the human eye by continuously capturing the changes in a visual scene. The information captured by the camera stimulates a 150 electrode epi-retinal implant, surgically inserted on to the surface of the retina, to send image signals to the brain.

The safety and effectiveness of the IRIS®II system in people with severe vision loss due to RP, choroideremia or cone-rod dystrophy is currently being evaluated in the IRIS®II clinical trial being conducted at several ophthalmological centres of excellence in Europe (NCT02670980).

PRIMA high-resolution photovoltaic retinal prosthetic system

The PRIMA bionic vision system is a sub-retinal miniaturized wireless photovoltaic implant platform (Pixium Vision, Paris, France). The PRIMA system is currently being evaluated in clinical studies for the treatment of vision loss among patients with dry age-related macular degeneration (NCT03333954 and NCT03392324). However, there are also plans to evaluate PRIMA in patients with vision loss due to RP in the future.

Retina Implant

The Retina Implant Alpha AMS (Retina Implant AG, Reutlingen, Germany) is a sub-retinal implant device that received European CE mark approval for commercial use in mid-2013. The device consists of a small microchip, similar to a digital camera, which is surgically implanted underneath the retina. By electrically stimulating the overlying retinal layers that are still functional, the microchip is able to replace the function of the degenerated photoreceptors (rods and cones), helping to partially restore functional eye sight.

Suprachoroidal Retinal Prosthesis

The Suprachoroidal Retinal Prosthesis  (Bionic Vision Australia, Melbourne, Australia) is another retinal implant device product under development. The implant is placed between the posterior blood supply of the eye (choroid) and the outer white layer of the eye (sclera).

The pilot study of the 33-electrode prototype suprachoroidal implant found no unexpected intraocular serious adverse events in the three implanted patients with advanced RP Future studies will evaluate the efficacy and safety larger numbers of electrodes in larger cohorts of participants with profound vision loss from RP.

Optogenetics

Clinical studies in individuals with degenerations of the outer retina have shown that the Retina Implant Alpha AMS can restore limited visual function. The impact of the Retina Implant Alpha AMS on daily living of patients with inherited outer retinal layer degenerations is currently being evaluated by a study in France (NCT03561922). The safety and effectiveness of the device is also being currently being evaluated in patients who are blind due to RP in the United States (NCT03629899)

Optogenetic combines the use of gene therapy and optical technology to alter retinal cells that remain intact during the course IRDs so that they become responsive to light. By creating artificial photoreceptors using retinal cells that do not naturally light-sensitive, such as ganglion cells or bipolar cells, optogenetics may be used to help partially restore vision in areas of the retina where natural photoreceptor cells have become damaged by the disease.

This approach is already being evaluated in a clinical trial with RST-001 (Allergan), a first-in-class gene therapy application of optogenetics (NCT02556736) RST-001 is gene therapy that can be used to deliver a gene for a light-sensitive protein found in green algae (channelrhodopsin-2) to create new photosensors in retinal ganglion cells in order to potentially restore vision in patients with advanced RP.

Natural History Studies and Disease Registries

Because IRDs are rare and only affect a relatively small number of people, there may be gaps in our understanding about the natural course of these diseases. One approach that can be used to address these is to conduct natural history studies. Natural history studies follow a group of people with the disease usually over a period of several years in order characterize how a disease progresses over time. In the case of IRDs, natural history studies may capture valuable information on how disease progression rates may vary between patients with different genetic mutations. A clear understanding of the natural history of a disease is very important to ensure that clinical studies are appropriately designed to accurately measure the clinical benefits of new treatments

The establishment of disease registries for patients with IRDs is another important research development. A disease registry is a database that contains information from people diagnosed with a specific type of disease. My Retina Tracker® is free on-line, registry provided by the Foundation Fighting Blindness where patients diagnosed with an inherited retinal disorder can store information about the progression of their disease and how it impacts their life. These data are accessible to appropriately qualified researchers working in the field of IRDs and may also help them to identify people who may be eligible to participate in studies, although this is not guaranteed.

Click here for details of natural history studies currently enrolling patients.

As mentioned previously, IRDs are caused by mutations in genes that can be inherited. This led to the title of “Inherited Retinal Disease”. The genetics of IRDs can be very complex and in approximately one-third of cases, the genetic cause is not identified. However, ongoing research and genetic testing is advancing our knowledge of such genetic changes in order to find cures.

Genetic testing is crucial to establish the cause of the disease. Critically, it can determine if individuals have a specific mutation that may be treatable by specific gene therapies. Furthermore, it can help inform about the potential risk to family members and identify other organs that might be affected (in the case of syndromic disease).

You can learn more about how genetic testing works, and what it can do, at our toolkit ‘SENDING A RED ALERT!’, intended to inform those with rare eye diseases about genetic testing services: http://www.retina-international.org/toolkit-redalert

You can learn more about inheritance patterns here

Genetic testing can be necessary for participation in clinical trials for IRDs. Numerous clinical trials are currently evaluating the safety and effectiveness of gene therapy in several IRDs, including LCA, X-linked juvenile retinoschisis, RP, choroideremia, achromatopsia, and Leber Hereditary Optic Neuropathy. You can find a list of current trials related to IRDs here. You can also find trials by searching on the Clinical Trials website that lists most clinical trials, however it must be noted that not all trials listed on the clinicaltrials.gov website are valid or vetted. Therefore, we always advise that you talk with your ophthamologist about possible clinical trials participation.

Overview of Clinical Trials

New interventions, such as a new drug or medical device, need to be tested to make sure that they are safe for humans to use and that they are effective in treating the condition they are targeting. Clinical trials are the experiments used to test the safety and effectiveness of proposed new interventions. You can read more about the different phases of clinical trials here.

As clinical trials are used for testing something new and unproven, it is important to note that these are not yet considered to be ‘established treatments’ and so it is more appropriate to refer to them as ‘interventions’.

While people participate in clinical trials with the hope that the intervention will be beneficial to them, there is often the possibility that an individual will receive a placebo or fake intervention rather than the intervention itself. The placebo is an important part of clinical trials because it can show where the intervention itself had a true effect or whether another component of the trial had an effect. As it is not known whether the intervention is safe or effective, there is the possibility that it may have no effect or even cause harm.

Clinical trial participants, therefore, need to be fully aware of the possible effects of the intervention as well the possibility of unpredictable outcomes. It is important for participants to understand that they are partaking in research with the goal of evaluation if the intervention is effective, harmful, or has no effect different to other options already available. This should be all part of the informed consent process. You can find out more about what questions to ask for partaking in clinical trials here.

Numerous clinical trials are currently evaluating the safety and effectiveness of gene therapy in several IRDs, including LCA, X-linked juvenile retinoschisis, RP, choroideremia, achromatopsia, and Leber Hereditary Optic Neuropathy. You can find a list of current trials related to IRDs here. You can also find trials by searching on the website that lists most clinical trials, however it must be noted that not all trials listed on the clinicaltrials.gov website are valid or vetted, and so we always advise that you talk with your ophthamologist about possible clinical trials participation.

Keeping updated

Regular visits to your eye doctor can also make you aware of current advances as we learn more about these conditions.

To stay up-to-date of clinical trials of investigational therapies, natural history studies, or disease registries in your country, please visit ClinicalTrials.gov, see our list of Ongoing Clinical Trials, or contact your local patient organisation. Retina International’s member organisations are a great place to start http://www.retina-international.org/our-members