An Oxford University study has found that reducing the tendency of vitamin A to form toxic clumps could slow down retinal degenerative diseases such as Stargardt disease, a condition that leads to blindness in children and young adults, and in age-related macular degeneration.
People usually associate vitamin A as being good for the eyes, but the study found that in patients with Stargardt disease, vitamin A transforms into toxic compounds, which cause chronic inflammation, premature ageing of the retina and vision loss.
Stargardt disease affects around 1 in 10,000 people and begins in childhood, leading to progressive loss of central vision. The condition is linked to defects on a gene known as ABCA4. In Stargardt disease, the retina ages prematurely and granules called ‘lipofuscin’ accumulate. This accumulation of lipofuscin in the retinal pigment epithelium precedes retinal degenerations and dystrophies responsible for blindness-causing retinal diseases. The mechanism behind lipofuscin formation in the retina or in any tissue is poorly understood.
To date, there is no treatment for Stargardt disease, but a team led by Prof Peter Charbel Issa, a Professor at the University of Bonn, used genetically engineered mice to look at one possible cause of the premature aging of the retina in Stargardt disease. Collaborating with Dr Ilyas Washington, a chemist at Columbia University in New York City, along with others from Oxford, he team hypothesised that the degeneration was triggered by the formation of toxic clumps derived from vitamin A, which form through a process called ‘dimerization’.
To test this theory they used a modified vitamin A, which had deuterium atoms in place of three hydrogen atoms at a critical position on the vitamin A molecule. The modified vitamin A was administered in the diet of mice with the Stargardt genetic defect. The incorporation of deuterium atoms on the vitamin prevented it from clumping. As a result, lipofuscin formation was dramatically reduced along with inflammation, and progression of Stargardt disease was prevented. The treatment was also shown to be safe in both mutant and normal mice.
The authors discovered that Vitamin A dimerization is responsible for more than 50% of the lipofuscin found in the RPE. While others had suggested it might be a cause, they have confirmed that it is an important factor. If the rate of vitamin A dimerization can be reduced, it could reduce the genetically-induced build-up of lipofuscin and slow down the progress of retinal degeneration in diseases such as Stargardt and age-related macular degeneration.
The authors also wanted to check if altered vitamin A could cause any side-effects in humans that might affect sight in some another way, for example by damaging peripheral or low-light vision. However, tests showed that this was not the case – there was no adverse outcome in both normal and mutant mice fed the deuterated vitamin A.
Sources: Univ of Oxford PNAS
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Stargardt disease affects around 1 in 10,000 people and begins in childhood, leading to progressive loss of central vision. The condition is linked to defects on a gene known as ABCA4. In Stargardt disease, the retina ages prematurely and granules called ‘lipofuscin’ accumulate. This accumulation of lipofuscin in the retinal pigment epithelium precedes retinal degenerations and dystrophies responsible for blindness-causing retinal diseases. The mechanism behind lipofuscin formation in the retina or in any tissue is poorly understood.
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| (c) http://webvision.med.utah.edu |
To test this theory they used a modified vitamin A, which had deuterium atoms in place of three hydrogen atoms at a critical position on the vitamin A molecule. The modified vitamin A was administered in the diet of mice with the Stargardt genetic defect. The incorporation of deuterium atoms on the vitamin prevented it from clumping. As a result, lipofuscin formation was dramatically reduced along with inflammation, and progression of Stargardt disease was prevented. The treatment was also shown to be safe in both mutant and normal mice.
The authors discovered that Vitamin A dimerization is responsible for more than 50% of the lipofuscin found in the RPE. While others had suggested it might be a cause, they have confirmed that it is an important factor. If the rate of vitamin A dimerization can be reduced, it could reduce the genetically-induced build-up of lipofuscin and slow down the progress of retinal degeneration in diseases such as Stargardt and age-related macular degeneration.
The authors also wanted to check if altered vitamin A could cause any side-effects in humans that might affect sight in some another way, for example by damaging peripheral or low-light vision. However, tests showed that this was not the case – there was no adverse outcome in both normal and mutant mice fed the deuterated vitamin A.
Sources: Univ of Oxford PNAS
More about Retina Global here.
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