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 is 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 is planning a Phase I/II 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.
Opthotech are planning a Phase I/II trial of an intravitreal 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 metabolites. The trial is scheduled to start at the end of 2017.
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 has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) to a drug to help treat Stargardt Disease (Oct 30th 2017).
The drug known as LBS-008, is designed to prevent the build-up of a toxin in the eye called lipofuscin, that causes damage to the retina in Stargardt Disease. Phase I clinical trials are scheduled to start in 2018.
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
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.