RPE65: Vision, Blindness and Hope

Thu, 01/24/2013 - 10:35

Retinal pigment epithelium-specific 65 kDa protein (RPE65) is an essential vision protein, and so mutations in the RPE65 gene cause blindness. However, clinical trials using gene therapy to treat patients with a defective RPE65 gene suggest that some vision may be restored.

Our eyes detect light via pigments in rod and cone photoreceptor cells. These pigments consist of an opsin protein (a 7-transmembrane, G protein-coupled receptor) with a bound 11-cis retinal chromophore. The 11-cis retinal is the photosensitive component, undergoing photoisomerization to all-trans-retinal. This induces a conformational change in the opsin, activating it and initiating a signal transduction cascade. The 11-cis form of the retinal must be regenerated for the pigment molecule to detect light again, and RPE65 is vital for this process.

Studies of rod cells have built up our understanding of the multi-step pathway that achieves this regeneration, called the visual cycle. The all-trans-retinal is released from the opsin, and is transported out of the photoreceptor cell into the adjacent retinal pigment epithelium (RPE), where RPE65 and other enzymes are located. RPE65 is thought to be the isomerohydrolase in the cycle, which converts all-trans retinyl ester to 11-cis retinol. When the regeneration of 11-cis retinal is completed, it is returned to the photoreceptor cell and binds to the opsin, ready to absorb the next photon of light. While the pathways of cones are less well understood, RPE65 has been shown to be vital for their function too. (RPE65 is actually expressed in the cones themselves.)

IHC analysis of RPE65 in mouse retina tissue IHC analysis of RPE65 in mouse retina tissue

It follows that mutations in the RPE65 gene are associated with severe vision impairments, including a subtype of LCA (Leber congenital amaurosis), an autosomal recessive disease. Sufferers of LCA have severely impaired vision, either from birth or following rapid degeneration of sight at an early age. Previously, there was no known treatment or cure, but three separate ongoing human trials using gene therapy to deliver normal RPE65 DNA (using the AAV viral vector) to the eyes of LCA patients with the defective RPE65 gene have had encouraging results. The reports of these clinical trials have indicated that this method of gene therapy is safe, and there was some improvement in the patients’ vision. These promising findings pave the way for gene therapy to treat other inherited disorders.

Novus Biologicals offers a number of antibodies for RPE65 and many other vision proteins for your research needs.

  1. PMID: 19373675
  2. PMID: 22644094

Novus Biologicals offers RPE65 reagents for your research needs including:

Written by Carly Hammond

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