Many thanks to Professor Michel Michaelides BSc MB BS MD FRCOphth FACs of UCL Institute of Ophthalmology and Moorfields Eye Hospital for his input and reviewing the Stargardt’s Research Page.
There are many research trials exploring Stargardt’s and potential future treatments and cures.
Here is information about the main ongoing research related to Stargardt’s:
Gene Therapy is a research technique where the underlying genetic basis of a disease is addressed in order to treat or prevent a disease.
There are a few ways this can be done including:
- introducing a “healthy” copy of the faulty gene – an approach commonly adopted for ‘recessive’ diseases where often there is a deficiency due to the genetic fault. This is the case in Stargardt disease (STGD1).
- “switching off” the faulty gene that in ‘dominant’ disease is often producing a toxic product causing harm.
A phase I/II clinical trial of gene therapy to replace a normal copy of the gene that causes Stargardt disease, ABCA4, is currently underway.
Sanofi are conducting the trial, which is taking place in Portland, U.S. (Oregon Health and Science University) and Paris, France (Centre National d’Ophtalmologie des Quinze-Vingts).
A healthy copy of the gene is being surgically administered under the retina with the use of a vector in the form of a virus, which will carry the healthy copy of the ABCA4 gene and deliver it to the light sensitive cells, the photoreceptors, in the outer retina.
There have been no safety concerns to date, with some evidence of benefit in a small number of patients with early mild Stargardt disease. The trial is on-going.
More information can be found at:
Other Phase I/II gene therapy trials for Stargardt disease are being developed by other pharmaceutical companies including Shire and NightStaRx.
Stem Cell therapy
Stem cells are notable cells that are produced in the body and have the amazing potential to transform into many different cell types during growth and early life.
There are 2 main different types of stem cells that are most likely to be used for stem cell therapy:
- Induced pluripotent (iPS cells). These cells are engineered in the lab.
Stem cell clinical trials for Stargardt’s Disease
Ocata Therapeutics (formerly Advanced Cell Technology, ACT) have conducted a clinical trial in patients with advanced Stargardt disease using human embryonic stem cell derived retinal pigment epithelial (RPE) cells. These cells were injected under the retina. RPE cells whose role is to support and nourish the photoreceptors (rods and cones) in the retina, degenerate in Stargardt disease, often before photoreceptor cell loss. The idea is that by replacing healthy RPE cells, this will stop or slow down photoreceptor cell loss and thereby slow/halt vision loss.
Early results have been promising with a successful safety trial, conducted in the USA and UK.
Ocata Therapeutics has since been taken over by Astellas Pharma – with a new Phase I/II trial in Stargardt disease of an improved RPE cell line being developed.
Opsis Therapeutics are developing a clinical trial where a patch consisting of retinal cells derived from stem cells will be placed at the back of the eye with the hope to restore vision. Dr. David Gamm, MD, PhD at the University of Wisconsin-Madison is leading this study with a team of researchers.
Dr Anai Gonzalez-Cordero, in association with Professors Robin Ali and Rachael Pearson, at UCL Institute of Ophthalmology, is working on a type of stem cell called an induced pluripotent stem cell or iPS cell. iPS cells are generated in a lab from tissue samples donated by patients. By taking a sample of tissue, such as blood or skin, these cells can be reprogrammed and turned into stem cells, which can subsequently be turned into photoreceptors for potential transplantation in the future.
Dr Anai Gonzalez- Cordero is currently working on producing retinal cells from patients with Stargardt disease. By studying these cells, it is hoped we can have a better idea of how the faulty Stargardt gene causes retinal cells to be damaged and subsequently be lost. It can also help with developing potentially new treatments as these cells can be tested with drugs or viral vectors (gene therapy) to explore the safety and any beneficial effects of these approaches.
There are a number of companies that are looking at using various different drugs as a form of treatment for Stargardt disease.
Professor Andrew Lotery, a professor of ophthalmology at the University of Southampton and consultant ophthalmologist at University Hospital Southampton NHS Foundation Trust, is the first in the UK to be trialling a pioneering drug in a £5 million study with colleagues at centres in the Netherlands, Italy, Germany and Norway. The drug remofuscin, which is taken orally, removes the fat deposits, known as lipofuscin, which build up in the back of the eye. More information can be found on https://www.southampton.ac.uk/medicine/news/2018/02/13-02-2018-andrew-lotery.page
The cause of Stargardt disease is faults in the ABCA4 gene. The ABCA4 gene’s role is to produce a protein called a Rim protein. The Rim protein’s role is to help transport Vitamin A molecules (needed to form the light sensitive pigment in rod and cone cells) from the photoreceptors back to RPE cells, where these Vitamin A molecules are recycled to be reused for vision.
However, in Stargardt’s, the faulty ABCA4 gene produces a Rim protein that either is non-functional or has significantly reduced function, and thereby disrupts this process of transport. The Vitamin A molecules therefore tend to accumulate in the photoreceptors/RPE cells rather than being transported and recycled. This causes a waste management problem resulting in build-up of toxic products, including ‘Vitamin A dimers’, which are believed to be involved in vision loss, by damaging RPE cells and photoreceptors.
Alkeus Pharmaceuticals have developed an oral drug called ALK-001 which aims to prevent the formation of these toxic Vitamin dimers in the retina.
They have successfully completed their safety trial and now have started Phase II of their clinical trial in adults and children (n=50) with Stargardt disease. The trial is fully enrolled and the last patient visit is anticipated in July 2019.
Acucela has started enrolling patients (November 2018) for the Phase 3 placebo controlled clinical trial for the oral drug called Emixustat which has been developed to slow the build-up of toxic waste products which are believed to be responsible for the vision loss in Stargardt disease.
Moorfields Eye Hospital will be the primary trial site in the UK.
Ophthotech is conducting a randomized, controlled clinical trial assessing the safety and efficacy of Zimura® (avacincaptad pegol), an intravitreal (injected into the vitreous gel of the eye) agent targeting the Complement inflammation system which is believed to be activated and cause damage to retinal cells following the accumulation of vitamin A-related toxic waste products.
Moorfields Eye Hospital will be the primary trial site in the UK.
Nacuity Pharmaceuticals are planning a Phase II trial with a drug called NACA which is derived from N-acetylcysteine in 2018. Phase I is on-going.
N-acetylcysteine is an antioxidant (hinders oxygen damage to the body).
N-acetylcysteine-amide (NACA) is designed to slow vision loss by protecting retinal cells from oxidative stress. Oxidative stress is a process that is thought to accelerate and exacerbate degeneration in many inherited retinal conditions.
Lin Bioscience will be conducting a Phase 1 placebo-controlled safety clinical trial.
The drug known as LBS-008, is designed to prevent the build-up of toxic waste products in the eye (lipofuscin and lipofuscin-related material), that causes damage to the retina in Stargardt Disease.
Natural History Studies
The Foundation Fighting Blindness Clinical Research Institute has funded a $6 million multicentre international (USA, UK, France and Germany) natural history study (ProgStar) for people affected by Stargardt disease.
It has 3 primary goals:
- Determine the best outcome measures to accelerate evaluation of emerging treatments in clinical trials
- better understand disease progression for selecting future clinical trial participants
- identify potential participants for forthcoming clinical trials.
The natural history study uses retinal imaging and functional testing of patients with Stargardt’s disease who have been seen every 6 months for two years with the hope to get a better idea of the prognosis and how the disease progresses. Predominantly adults with milder Stargardt disease were recruited.
There are many published ProgStar papers . Here is a link to one of them:
Professor Michel Michaelides who is a Professor of Ophthalmology at the UCL Institute of Ophthalmology and Consultant Ophthalmologist at Moorfields Eye Hospital is also leading a Natural History Study (part funded by the Macular Society – UK), which is a longitudinal study over 2 years. More than 70 genetically confirmed patients (adults and children) with Stargardt disease are participating and have had detailed serial structural and functional testing. The patients will be reviewed every 6 months for 2 years after an initial baseline assessment.
Systematic Review of Treatments for Dry AMD and Stargardt’s
Norman Waugh and a team of colleagues from the University of Warwick have published a systematic review of treatments for dry AMD and Stargardt’s (May 2018). They reviewed all the relevant studies in Stargardt’s and made some recommendations:
- NIHR may want to consider a trial of fenretinide to reduce damage to the macula and a pilot study of the nutritional supplements, lutein and zeaxanthin, to see if they protect the macula.
- It could be useful for research studies to look for changes earlier in the diseases before vision is affected.
What do Phases mean in a clinical trial?
A clinical trial is normally divided into 4 phases to test its safety and effectiveness.
Phase I will test the safety of a drug, observing the side effects of it and will typically test a small number of people, usually who are healthy volunteers.
Phase II will normally test the effectiveness of the drug on a larger group of people who have the disease, again looking at safety and if the treatment has an effect on the condition.
Phase III will be tested on an even larger population and may involve using a placebo as well as the drug to see the effect of the treatment. The participants will not usually be aware if they have been given the placebo or the drug that is being tested.
Phase IV is the final phase and is usually done after the treatment has been approved by the drug regulatory authorities. It will study the effect of the drug on a range of people and look at any long-term side effects.
More information can be found at:
Information about clinical trials that are currently being conducted worldwide can be found on www.clinicaltrials.gov and can be searched by condition and trial location.
In September 2018, Stargardt’s Connected organised a Nutrition Chat for Stargardt’s families. The aim was to discuss what are the questions and concerns people have about nutrition and its effect on Stargardt’s. The discussion was led by Dr. Andi Skilton from NIHR Moorfields Biomedical Research Centre and Dr Rosie Gilbert, an Ophthalmologist from Moorfields Eye Hospital.
As a summary, the main points from the discussion were:
- It is important not to completely cut out Vitamin A from our diets as it is needed for the functioning of other parts of the body.
- There is no evidence that ‘natural’ vitamin A precursors in food e.g. betacarotene found in naturally orange foods such as carrots and oranges or their juice, or green vegetables, can cause problems in the retina, so it is not necessary to stop eating these foods.
- It is best to avoid Vitamin A supplements (either isolated or as part of multi-vitamins) as these will contain a relatively high dose of Vitamin A compared to what is taken in a normal diet
- Preformed or synthetic vitamin A found as additives in food, or stored in high concentration in animal organs, such as liver, might be avoided, where possible – for example, by choosing higher quality minced meat such as minced steak, which has lower offal and synthetic additive content. Look out for products which may be fortified with vitamins and minerals e.g. breakfast cereals and avoid if it is fortified with Vitamin A.
- Foods containing lutein and zeaxanthin are thought to be good for the macula, and include foods such as green leafy vegetables like kale. Lutein is best absorbed with fat so the best way to cook foods such as kale is to cook it in oil.
- Certain popular ‘superfoods’ such as turmeric and saffron may have general health benefits due to antioxidant content, but we do not advise people to take an excessive intake, just to enjoy as part of a healthy diet with lots of fresh, unprocessed food.
- Most importantly, it is best to have a well-balanced and healthy diet and a positive attitude towards the food we eat.
While there isn’t any conclusive research about what people with Stargardt’s should and shouldn’t eat; Stargardt’s Connected will be liaising with some experts in nutrition to help put together a leaflet that will include some recommendations based on best current thinking.
I would like to say a huge thank you to Dr Andi Skilton and Dr Rosie Gilbert for organising and leading the Nutrition Chat which was really useful and stimulated some really interesting discussion. Thank you also for their help and input in reviewing the summary and to Professor Michel Michaelides from Moorfields Eye Hospital for his input too.