Study Sheds Light on the Complexity of Gene Therapy for Congenital Blindness

Independent clinical trials, including one conducted at the Scheie Eye Institute at the Perelman School of Medicine, have reported safety and efficacy for Leber congenital amaurosis (LCA), a congenital form of blindness caused by mutations in a gene (RPE65) required for recycling vitamin A in the retina. Inherited retinal degenerative diseases were previously considered untreatable and incurable. There were early improvements in vision observed in the trials, but a key question about the long-term efficacy of gene therapy for curing the retinal degeneration in LCA has remained unanswered. Now, new research from the Scheie Eye Institute, published this week in the Proceedings of the National Academy of Sciences, finds that gene therapy for LCA shows enduring improvement in vision but also advancing degeneration of affected retinal cells, both in LCA patients and animal models of the same condition.

LCA disease from RPE65 mutations has two-components: a biochemical blockade leading to impaired vision, and a progressive loss of the light-sensing photoreceptor cells throughout life of the affected patient. The authors of the new study explain that until now gene therapy has been optimistically assumed, but not proven, to solve both disease components at the same time.

“We all hoped that the gene injections cured both components – re-establishing the cycle of vision and also preventing further loss of cells to the second disease component” said Artur V. Cideciyan, PhD, lead author and co-investigator of an LCA clinical trial at Penn.

Yet, when the otherwise invisible cell layers of the retina were measured by optical imaging in clinical trial participants serially over many years, the rate of cell loss was the same in treated and untreated regions. “In other words, gene therapy improved vision but did not slow or halt the progression of cell loss,” commented Cideciyan.

“These unexpected observations should help to advance the current treatment by making it better and longer lasting,” commented co-author Samuel G. Jacobson, MD, PhD, principal investigator of the clinical trial. “Slowing cell loss in different retinal degenerations has been a major research direction long before the current gene therapy trials. Now, the two directions must converge to ensure the longevity of the beneficial visual effects in this form of LCA.”

(Image: bigstockphoto)

New understanding of brain’s early spatial development

Researchers at the University of Bath have uncovered a new understanding of how the brain develops its sense of space by working with blind people.

The researchers from the University’s Department of Psychology found that people who lose their sight later in life use a different method of following directions to those who are born without sight. This means that the brain needs to have a visual experience early on in life in order to build a visual perspective, or frame of reference, to know what is where.

The researchers carried out a study with participants including those who were congenitally blind; those who became blind later in life; and others who were sighted, to learn which methods the different groups used to remember where things are.

The study revealed that people who have been sighted and then become blind use a ‘allocentric’ reference frame, meaning they remember locations as they are positioned relative to one another, and this is the same as sighted people who do this task, even when blindfolded.

In contrast congenitally blind participants preferred an ‘egocentric’ reference frame meaning they first remember a starting point at home and then store a memory of the locations from the home location. Dr Michael Proulx who led the study said the results help us to understand more about the role of a critical period for developmental vision on spatial cognition and brain organisation.

He said: “In our study we were curious as to whether having visual experience during child development was key to creating the structures in the brain to support such an allocentric reference frame. First we found an interesting difference between the congenitally blind and sighted people: although the sighted people preferred the allocentric, reference frame, the congenitally blind participants preferred the self-centred or egocentric reference frame for remembering locations.

“The important piece of the puzzle, however, was whether the late blind people would perform like the congenitally blind, showing that current visual experience matters, or like the sighted, showing the role of early visual experience. The results were clear: the late blind performed the same as the sighted participants. Therefore having the experience of vision early in life lays the groundwork in the brain for the representation of locations in a different reference frame than that found in people who never had visual experience.”

All of the participants of the study were blindfolded and then walked to the locations of objects in a large room. They were later tested on a computer with a virtual pointing task that asked them to remember objects in the room relative to the other object locations.

Dr Proulx and his colleagues are following up this finding with additional research to investigate how additional information, such as the texture or sound of the environment, might influence the frame of reference used.

This would allow for improved maps rendered in Braille or sound to be produced for visually impaired persons to use in public places, such as rail stations, or in new cities.

They are also examining the impact of visual experience on the neural basis for spatial learning and memory by examining how the congenitally blind and late blind brains represent spatial information in the absence of vision.