Neuroprotective approaches for choroideremia

Brief Lay Background

Choroideremia is an inherited disorder that causes sight loss and mostly affects men. Difficulties with night vision usually start in childhood and by late adulthood, vision is completely lost.

Choroideremia is caused by a mutation in a gene called CHM. There is currently no effective treatment for inherited choroideremia, but there are some gene therapy treatments in clinical trials. Gene therapy might not be suitable for some patients because it requires eye surgery, and it might not be successful for all patients with inherited choroideremia in the long term, and so other treatment options are urgently needed.

What problem/knowledge gap does it help address

Choroideremia is caused by a mutation in a gene called CHM. There is currently no effective treatment for inherited choroideremia, but there are some gene therapy treatments in clinical trials. Gene therapy will not always be possible or successful for all patients with inherited choroideremia, and so other treatment options are urgently needed.

Drugs that protect nerve cells (neuroprotectants) have shown promise for slowing sight loss in people with different types of inherited retinal disease. This project will explore whether nerve protecting drugs can protect cells and prevent sight loss in a model of inherited choroideremia.

Dr Moosajee has genetically engineered zebrafish to carry the same mutation in the CHM gene that is seen in patients. Zebrafish with mutations in this gene develop the same disease in the retina, but it develops much more quickly – in around 4-5 days. This makes it possible to rapidly test drugs that could slow this disease process down.

Aim of the research project

To assess if cell damage can be halted or slowed using neuroprotectant drugs and if this can protect the retina in zebrafish.

Key procedures/objectives

Four nerve protecting drugs will be tested in zebrafish with choroideremia:  

1. Curcumin – this has anti-inflammatory properties and is being tested in clinical trials for several inherited eye diseases.
2. Levodopa – it is believed this might restore low levels of dopamine. Low dopamine has a negative effect on nerve cell survival and function. Levodopa is being tested in clinical trials with people with retinitis pigmentosa. 
3. N-acetylcysteinamide (NACA) – this is an antioxidant, and it has reached the second stage of clinical testing in people with retinitis pigmentosa. 
4. Tauroursodeoxycholic acid (TUDCA) – this stops cell death and has been shown to preserve function in the retina in animals. It is also being tested in clinical trials for motor neurone disease.

There are two objectives for each of the four neuroprotectants: 

1. Determine the optimal safe and tolerable dose for each of four neuroprotectants in healthy zebrafish without the CHM mutation.
2. Determine the safest and most effective dose in zebrafish with the CHM mutation. The zebrafish eyes will be studied in detail to see whether the drugs have protected against loss of cells in the retina.

Potential impact on people with sight loss

The drugs being tested have already been investigated in early clinical trials for safety. This means that if any of the drugs are successful in this study at protecting nerve cells in the eye, they could be quickly adopted for testing in patients in a clinical trial. This could provide months or years of useful vision to people with inherited choroideremia, allowing them to continue to work, and maintain their independence and quality of life.