University of Edinburgh

Medical Information on Gene Therapy for Inherited Retinal Diseases

by Dr Andrew Blaikie for VI Scotland

This document is written with the minimum use of medical terms and jargon. It is impossible to avoid all medical terms but where we have used them we have attempted to explain them as clearly as we can. Although the information is intended to describe most aspects of the condition each child is different and there will always be exceptions to the rule. As far as we can determine these pages are true and accurate and have been written in good faith.

What this Information is not for

This document is not a substitute for a consultation with a Health Professional and should not be used as a means of diagnosing a condition.

We hope the Information will help you to:

  • Have a better understanding of the condition
  • Know what tests and treatments are normally available
  • Know when to seek professional advice
  • Be able to discuss the condition in a more informed way
  • Make the most of consultations with carers, teachers and health professionals
  • Be reassured and more able to cope

Due to staffing limitations we are not able to offer telephone or email advice to parents of children.

Medical Information on Gene Therapy for Inherited Retinal Diseases

What we see is made in the brain from signals given to it by the eyes. What we see is in fact made in the brain. The brain makes sight from signals given to it by the eyes.

What is the normal structure of the eye?

The eye is made of three parts.

  • A light focussing bit at the front (cornea and lens).
  • A light sensitive film at the back of the eye (retina).
  • A large collection of communication wires to the brain (optic nerve).

A curved window called the cornea first focuses the light. The light then passes through a hole called the pupil. A circle of muscle called the iris surrounds the pupil. The iris is the coloured part of the eye. The light is then focused onto the back of the eye by a lens. Tiny light sensitive patches (photoreceptors) cover the back of the eye. These photoreceptors collect information about the visual world. There are two types of photoreceptors named by their shape when looked at in fine detail. They are called ‘rods’ and ‘cones’.

Rod and Cone Photoreceptors are good at seeing different things

Rods are good at ‘seeing’:

  • things that move
  • in the dark
  • but only in black and white
  • and in less detail.

┬áCones are good at ‘seeing’:

  • things that are still
  • in daylight
  • in colour
  • and in fine detail.

The covering of rod and cone photoreceptors at the back of the eye makes a thin film called the retina. The central bit of the retina is made up of cones. They help us see in fine detail the central bit of vision that we use for reading, looking at photographs and recognising faces. The area of the retina around the edges is made up of rods. The rods see the surrounding bits of vision and help us to see as we walk around and not bump into things especially in the dark. Each photoreceptor sends its signals down very fine wires to the brain. The collection of wires joining each eye to the brain is called the optic nerve. The information then travels to many different special ‘vision’ parts of the brain. All parts of the brain and eye need to be present and working for us to see normally.

Inherited retinal diseases

Most nerve cells, including the retina, cannot repair themselves if damaged. This means damaged areas of the retina cannot regain function. The most common cause of damage in childhood is by inheriting a ‘misprint’ in the genes. Childhood visual impairment is rare with roughly 20 to 40 children in every 10,000 having significant visual difficulties. Inherited retinal conditions account for about 10 to 20 per cent of these cases. These conditions include:

Treatment of inherited retinal diseases

Before now the management of children with poor eyesight from retinal conditions involved overcoming visual difficulties by practical means such as enlarging text or using magnifying aids. Recently, however, important leaps have been made in gene therapy for these conditions. This has led to successful trials in animal models and now humans that appear to be leading to treatments for certain inherited retinal conditions.

Gene therapy

As the body cannot re-write genetic misprints, the only way to fix the genes is to try to introduce normal-working genes or DNA into affected cells. The most successful research uses a virus to transport the normal working gene into the affected retina. It is important to note that the only virus genes that remain are those that help the treatment gene get into the cell. The normal working genes are then put into the virus capsule. This is then injected into the eye. The virus enters the retinal cells where it multiplies, creating more copies of the normal gene. This effect can last, so sometimes only one injection may be needed.

The viruses used do not normally cause damage or disease to the eye. In fact, the eye is an ideal place for gene therapy to work. This is because less virus material is needed here, and the eyes immune system is sealed off from the rest of the body. Also, because most retinal cells do not divide, the risk of developing cancer is very low, compared with similar treatments to other parts of the body. Also, during testing, the other eye can be looked at to directly compare any benefit from the treatment.

One of the challenges is that inherited retinal diseases are caused by a huge number of different genes. This means specific gene therapy is necessary for each genetic misprint. Another difficulty is the size of a normal working gene that needs to be transplanted. Some of the retinal genes are very long and complicated. The smaller the gene the better, as a smaller viral capsule can be used which reduces the likelihood of the body's immune system attacking the new material.

Successful research

The first clinical trials for retinal gene therapy were on retinoblastoma and age-related macular degeneration. These were very important in showing that this kind of treatment is safe. However, the trials were too small to show any definite benefit in these conditions.

  • Leber's Congenital Amaurosis (LCA) - This is caused by mutations in an enzyme called RPE65. Researchers have successfully used viruses to introduce normal genes into human retinas affected with LCA. The most recently published data from Pennsylvania (in the United States) involved 15 patients (aged 11 to 30 years old) who have now been followed up for over 3 years after one treatment. All patients had some improvement in their vision. In fact those who started with the worst vision improved the most. Some of the patients have had their second eye treated which has also improved. They also found improved sensitivity of the photoreceptor retinal nerve cells, improvement to the structure of the retina, and improved response of the pupils to light. The only side effects were from the surgical procedure itself (the injection). Other human trials are ongoing in the UK and USA.
  • Stargardt's Disease - Lipofuscin is a substance found in high concentrations in the retinas of those affected with Stargardt’s. In mouse trials, after injection with a normal gene there was an increase in the number of retinal cells that carried a normal electrical signal. Also, those given just a single injection showed reduction in lipofuscin. There was still some effect at one year after initial injection. This research has led to human trials which are ongoing.
  • Leber's Hereditary Optic Neuropathy (LHON) - This condition is caused by misprints in mitochondrial DNA. This type of DNA is not in the nucleus of the cell, so is more inaccessible to viruses. Studies in mice have shown that by introducing healthy mitochondrial genes into the cell nucleus the nerve cells can start working again even though the genes are in the ‘wrong’ place. An American centre is now recruiting for human trials.
  • Retinitis Pigmentosa (RP) - This is an umbrella term for a large number of retinal disorders characterised by damage to retinal cells and reduction in vision. They are caused by a huge number of genetic misprints, which means difficulty in managing with targeted gene therapy. “Non-specific” gene therapy focussed on improving the general health or limiting damage to the retina may help stabilise visual loss or improve vision. A trial in one form of RP in Saudi Arabia is proving promising. Usher's syndrome is a condition which encompasses retinitis pigmentosa and deafness. A human trial for a type of this disease is underway in America and France began in March 2012
  • Choroideraemia - This inherited retinal disease is ‘X-linked’, which means it almost exclusively affects males. It doesn't only damage the retina but also the choroid layer below. This layer contains blood vessels which provide nutrients and oxygen to the eye. A trial is currently underway in London and Oxford which aims to prevent progression of the disease with gene therapy. Early results show it to be safe.
  • Others - Gene therapy trials are also currently underway for other eye conditions such as retinoblastoma, Usher's syndrome, age-related macular degeneration, uveitis, and glaucoma.

The Future

Gene therapy clearly shows great promise for the future for people with inherited retinal diseases. The research so far suggests that in general those treated at an earlier stage of their disease do better (before the retina becomes too damaged). This includes children, and older patients, as long as the condition is at an early stage of development. This means early diagnosis and referral to specialist centres will be important to maximise any benefit from treatment.

January 2013

Who wrote these documents?

These pages are the consensus of opinion of many different people They include parents of visually impaired children, visually impaired children themselves, Community Paediatricians, Ophthalmologists, Educationalists and Psychologists.

The main author and person responsible for their content is Dr Andrew Blaikie who was an Ophthalmology Research Fellow with Visual Impairment Scotland and is a member of the Royal College of Ophthalmologists.

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