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.

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: 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.

Retinal Prostheses

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.