Category: Research

Month: 18 Apr 2017

Issue: not yet available

Long lasting retinal photo-switch restores visual function after a single intra-ocular injection.

Scientists based at the University of California, Berkeley, have published results of a study showing how a small molecule “photo-switch” –a molecule that changes conformation in response to light– may be capable of restoring vision in models of retinal degeneration. The research results, published in Scientific Reports (DOI: 10.1038/srep45487) describes a third generation molecule named “BENAQ”, capable to restoring retinal responses to white light of an intensity similar to ordinary daylight. A single intra-ocular injection of BENAQ appeared to photosensitize a blind retina for up to a month, re-establishing electrophysiological and behavioural responses with no signs of toxicity. BENAQ is described as a red-shifted K+ channel photo-switch exhibiting trans to cis photo-isomerization with visible light (450–550 nm) and relaxing rapidly to the trans configuration in the dark.

 

The BENAQ molecule was developed to overcome short-comings in similar photo-switch molecules called “DENAQ” and “AAQ” (all synthetic azobenzenes). The first generation switch required high-intensity UV light and had a short half-life making it unsuitable for intravitreal injection in the eye. The research team tested the more suitable DENAQ molecule in a rapidly degenerating RP model by using an electrode array to measure the effect of light on action potential firing of retinal ganglion cells (RGCs). A 2uL intravitreal injection of 300mM DENAQ photosensitized the retina causing a rapid response in firing from the majority of RGCs. However, it was found that retinal photosensitization with DENAQ required a relatively high dosage, in addition to which, the molecule tended to have a short half-life following treatment. The most recent version –BENAQ– represents an improved version, 20-fold more potent than DENAQ, according to the research team, and capable of restoring visual responses to the retina for up to 1 month following a single intraocular injection. In respect of safety, further experiments demonstrated that BENAQ was non-toxic to mice and rabbits at concentrations 10-fold higher than the concentration required to trigger light-sensitivity.

 

The experiments were performed on degenerating retinas of 3- to 6-month-old rd1 mice, a widely used laboratory model of Retinitis pigmentosa (RP), in which practically all rods and cones degenerate within approximately 4 weeks of birth. 100ms light pulses appeared sufficient to generate the recordable response while the minimum light intensity was 7X10^13 photons per sq. cm, roughly equivalent to daylight, suggesting clinical viability. As the therapeutic treatment of the RP models indicated that BENAQ was 20 times more potent that DENAQ in photosensitizing the retina, a clinical benefit may be possible with a dosing schedule similar or better to some anti-VEGF treatments currently in use to treat AMD.

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