Treating amblyopia by digestion of the extracellular matrix and stimulation of axonal growth in the visual cortex
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Biosciences
Abstract
The commonest visual disorder of children is amblyopia (lazy eye), which affects 2-4% of the population. This project explores potential avenues for treating amblyopia in adulthood.
Amblyopia is defined clinically as a deficit in visual acuity despite optimal refractive correction, due to some disruption of normal visual development during childhood. Amblyopia is usually treated by occlusion therapy (covering the good eye for a period of time to enforce the use of the amblyopic eye). The effectiveness of this procedure decreases with age. To date, it is not possible to restore normal vision in an amblyopic eye after the age of 8 years, the end of sensitive period of cortical plasticity. This project aims at restoring visual cortical plasticity in adulthood. We know that in the adult brain, the ability of neurons to form new connections is limited by a mesh of molecules surrounding them, the extracellular matrix, which becomes more and more rigid during adolescence. We plan to infuse enzymes into the visual cortex that will loosen up that matrix, and additional substances that are known to promote the outgrowth of neuronal processes. We hope that this combination strategy will reverse the loss of functional connections from the deprived eye to the visual cortex. We will employ functional brain imaging to assess whether visual cortex responses to stimulation of the amblyopic eye will have returned. We will test and refine our treatment using animals, and later on hope to develop it further for amblyopic patients who have suffered loss of vision in their good eye through illness or injury and have therefore become blind or severely visually impaired.
Amblyopia is defined clinically as a deficit in visual acuity despite optimal refractive correction, due to some disruption of normal visual development during childhood. Amblyopia is usually treated by occlusion therapy (covering the good eye for a period of time to enforce the use of the amblyopic eye). The effectiveness of this procedure decreases with age. To date, it is not possible to restore normal vision in an amblyopic eye after the age of 8 years, the end of sensitive period of cortical plasticity. This project aims at restoring visual cortical plasticity in adulthood. We know that in the adult brain, the ability of neurons to form new connections is limited by a mesh of molecules surrounding them, the extracellular matrix, which becomes more and more rigid during adolescence. We plan to infuse enzymes into the visual cortex that will loosen up that matrix, and additional substances that are known to promote the outgrowth of neuronal processes. We hope that this combination strategy will reverse the loss of functional connections from the deprived eye to the visual cortex. We will employ functional brain imaging to assess whether visual cortex responses to stimulation of the amblyopic eye will have returned. We will test and refine our treatment using animals, and later on hope to develop it further for amblyopic patients who have suffered loss of vision in their good eye through illness or injury and have therefore become blind or severely visually impaired.
Technical Summary
The commonest visual disorder of children is amblyopia. It is usually treated by occlusion therapy, but the effectiveness of this procedure decreases with age and is limited when applied after the age of 5 years. To date, it is not possible to restore normal vision in an amblyopic eye after the age of 8 years, the end of the critical period of visual cortical plasticity. This project aims at restoring visual cortical plasticity in adulthood in order to develop a treatment for amblyopia.
We will employ monocular deprivation by lid suture as the classical animal model for deprivation amblyopia in humans. We will attempt to reverse the loss of functional connections from the deprived eye to the primary visual cortex (V1) in adult animals. Our experimental design builds on recent work showing that the end of the critical period is precipitated by the aggregation of chondroitin sulphate proteoglycans (CSPGs) in the extracellular matrix into perineuronal nets, which have an inhibitory influence on cortical plasticity.
Animals will be monocularly deprived until the end of the critical period. The deprived eye will then be re-opened, and functional imaging will be employed to visualize ocular dominance patterns in V1; visually evoked potentials (VEPs) will be recorded to assess neural visual acuity. Control animals will receive no treatment but will be re-imaged at weekly intervals for a month to ascertain that no recovery of vision through the previously deprived eye occurs. In experimental animals, following the initial imaging session, small injections of chondroitinase will be made into V1. This enzyme digests CSPGs and has been shown to restore cortical plasticity. We expect to see a shift in ocular dominance towards the previously deprived eye and improved VEP responses to gratings of high spatial frequency over subsequent weeks.
In order to increase the effectiveness of this treatment, we will, in addition, facilitate cortical plasticity by promoting axonal outgrowth with a number of substances, which have shown promise in recent work on spinal cord injuries. These include the nerve growth factor BDNF, a phosphodiesterase inhibitor (which results in increased cAMP levels), and the nucleoside inosine. These substances will be infused into V1 using osmotic minipumps, starting on the day of re-opening of the deprived eye.
Any treatment regime that proves successful in the animal experiments will later be trialled on adult amblyopic patients who have lost vision in their good eye through illness or injury.
We will employ monocular deprivation by lid suture as the classical animal model for deprivation amblyopia in humans. We will attempt to reverse the loss of functional connections from the deprived eye to the primary visual cortex (V1) in adult animals. Our experimental design builds on recent work showing that the end of the critical period is precipitated by the aggregation of chondroitin sulphate proteoglycans (CSPGs) in the extracellular matrix into perineuronal nets, which have an inhibitory influence on cortical plasticity.
Animals will be monocularly deprived until the end of the critical period. The deprived eye will then be re-opened, and functional imaging will be employed to visualize ocular dominance patterns in V1; visually evoked potentials (VEPs) will be recorded to assess neural visual acuity. Control animals will receive no treatment but will be re-imaged at weekly intervals for a month to ascertain that no recovery of vision through the previously deprived eye occurs. In experimental animals, following the initial imaging session, small injections of chondroitinase will be made into V1. This enzyme digests CSPGs and has been shown to restore cortical plasticity. We expect to see a shift in ocular dominance towards the previously deprived eye and improved VEP responses to gratings of high spatial frequency over subsequent weeks.
In order to increase the effectiveness of this treatment, we will, in addition, facilitate cortical plasticity by promoting axonal outgrowth with a number of substances, which have shown promise in recent work on spinal cord injuries. These include the nerve growth factor BDNF, a phosphodiesterase inhibitor (which results in increased cAMP levels), and the nucleoside inosine. These substances will be infused into V1 using osmotic minipumps, starting on the day of re-opening of the deprived eye.
Any treatment regime that proves successful in the animal experiments will later be trialled on adult amblyopic patients who have lost vision in their good eye through illness or injury.
