Regaining vision with gene therapy using adeno-associated viruses

Attila Csordas — Tue, 23 Sep 2008 04:22:28 -0700

Description

Adeno-associated viruses (AAV) are more and more promising candidates as viral vectors for gene therapy. They are small and not pathogenic according to our current knowledge, causing very mild immune response and are able to stably integrate into the host genome's chromosome 19 at a a particular site even in non-dividing cells.

Using viral vectors made out of adeno-associated viruses researchers were able to fully restore the sight of 2 people suffering from Leber's Congenital Amaurosis, an incurable congenital blindness syndrome.

"The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy."

Biomedical Sciences and Biotechnology

Source

http://www.pnas.org/content/early/2008/09/19/0807027105.abstract
http://en.wikipedia.org/wiki/Adeno-associated_virus
http://blog.wired.com/wiredscience/2008/09/gene-therapy-bl.html

The neurons and some molecules that are involved in visual orientation in a complex environment

jorgemata — Wed, 28 May 2008 05:56:59 -0700

Description

Using a virtual-reality arena to present visual targets to walking fruitflies, researchers show that insects share our ability to remember where an object is even when it is temporarily out of sight. By testing flies deleted in specific subsets of neurons and genetically rescuing mutant animals deficient in learning, the researchers pin down the neurons and some of the molecules that are involved in the process.

Visual orientation in a complex environment requires that a target's spatial position be stored, in case it becomes temporarily out of sight - a faculty known as 'spatial working memory' in vertebrates. German researchers show, in this week's Nature, that flies can remember the position of an object for several seconds after it has been removed from their environment. The flies were temporarily lured away from the hidden target, yet were able to resume their aim for it thereafter. The researchers identify the neurons involved - GABAergic ring neurons - and show that the S6KII signalling pathway is required in these neurons for the spatial working memory to function.

The abstract says:

Flexible goal-driven orientation requires that the position of a target be stored, especially in case the target moves out of sight. The capability to retain, recall and integrate such positional information into guiding behaviour has been summarized under the term spatial working memory. This kind of memory contains specific details of the presence that are not necessarily part of a long-term memory. Neurophysiological studies in primates indicate that sustained activity of neurons encodes the sensory information even though the object is no longer present. Furthermore they suggest that dopamine transmits the respective input to the prefrontal cortex, and simultaneous suppression by GABA spatially restricts this neuronal activity. Here we show that Drosophila melanogaster possesses a similar spatial memory during locomotion. Using a new detour setup, we show that flies can remember the position of an object for several seconds after it has been removed from their environment. In this setup, flies are temporarily lured away from the direction towards their hidden target, yet they are thereafter able to aim for their former target. Furthermore, we find that the GABAergic (stainable with antibodies against GABA) ring neurons of the ellipsoid body in the central brain are necessary and their plasticity is sufficient for a functional spatial orientation memory in flies. We also find that the protein kinase S6KII (ignorant) is required in a distinct subset of ring neurons to display this memory. Conditional expression of S6KII in these neurons only in adults can restore the loss of the orientation memory of the ignorant mutant. The S6KII signalling pathway therefore seems to be acutely required in the ring neurons for spatial orientation memory in flies.

Future of neuroscience

Source

Analysis of a spatial orientation memory in Drosophila. Kirsa Neuser1, Tilman Triphan1, Markus Mronz1, Burkhard Poeck1 & Roland Strauss1. Nature, May 29, 2008. doi 10.1038/nature07003

1 Lehrstuhl fuer Genetik und Neurobiologie, Biozentrum, Universitaet Wuerzburg, Am Hubland, Wuerzburg, Germany.