A new route towards treatment to recover sight based on controlling the activity of small molecules
The groups of Pau Gorostiza, ICREA Research Professor at IBEC, and Amadeu Llebaria of IQAC-CSIC have developed molecules that can be applied as light-regulated molecular prostheses to help restore vision in cases of retinal degeneration.
Together with their collaborators at ICIQ, INA, IRB Barcelona, CIBER-BBN and the Miguel Hernández and Alcalá de Henares universities, the researchers reveal in Nature Communications today their development of a new class of light-regulated drug, targeted covalent photoswitches (TCPs), that act as prosthetic molecules that can restore photoresponses in degenerated retinas.
Light-regulated drugs like the ones developed in recent years by IBEC researchers in Pau’s Nanoprobes and Nanoswitches group can be photoswitched remotely – that is to say, their biological activity can be turned on and off using light. Now, the collaborators have achieved proteins from the neurons involved in vision that respond similarly to when they are under normal physiological conditions – in other words, they trigger a response when light is received. In this way, they could act as prosthetic molecules and restore the photoresponse of degenerating retinas.
Changing shape to receive light
“Under normal conditions, the photoreceptor cells of the eye – the rods and cones – are those that react to receive light and activate, in turn, other retinal cells. We’ve designed molecules that are activated by light: to receive light, they change shape, which modifies their interaction with neuronal receptors involved in sending visual signals to the brain,” explains ICAQ’s Amadeu Llebaria. “This first step demonstrates that the technique is possible; that these cells could replace the function of rods and cones when they are damaged.”
The molecules have been tested on the retinal tissues of blind mice, where they were observed to be activating the cells in the retina, which sent an electrical signal in response to receiving light. The in vitro tests were conducted by researchers from the Miguel Hernandez and Alcala de Henares universities.
In this way, the research open the way towards revolutionary new therapies based on the controlled activity of small molecules – although it will be a while before this can be applied to real-world patients.
Applications in different organisms
Until now, the type of molecules that can be photoswitched in endogenous receptors – those found naturally in the organism – have been photochromic ligands (PCLs), freely diffusible small molecules that act directly on these proteins. But they often display low specificity for their target, their remote control is limited to a narrow concentration range, and they are rendered less efficient by dilution in tissue. To avoid these drawbacks, photocontrol of these molecules can be confined to particular receptors; but this comes at the cost of genetic manipulation, which poses other limitations.
To overcome these problems, the researchers developed a new chemical strategy to photoswitch protein activity that has the advantages of attachment to the target, but can be applied to endogenous proteins without requiring genetic manipulation.
“Our TCPs might work in a variety of organisms, including human, for which limited (opto)genetic manipulation techniques are currently available. This prospect makes the results on retina photosensitization especially appealing,” says Pau Gorostiza of IBEC/ICREA.
This type of treatment, though far in the future, could help restore sensitivity to light and darkness with a drug. That would increase the quality of life for people with impaired vision due to retinal degeneration. “Compared to currently available methods to restore retinal photoresponses such as retinal implants, our TCPs can help avoid surgery and providing better coupling to photostimulation than a physical device, as well as shortening rehabilitation by taking advantage of natural processing in the retina,” concludes Pau.
Source article: M. Izquierdo-Serra, A. Bautista-Barrufet, A. Trapero, A. Garrido-Charles, A. Díaz-Tahoces, N. Camarero, S. Pittolo, S. Valbuena, A. Pérez-Jiménez, M. Gay, A. García-Moll, C. Rodríguez-Escrich, J. Lerma, P. de la Villa, E. Fernández, M. À. Pericàs, Amadeu Llebaria, & P. Gorostiza (2016). Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches. Nature Communications, epub ahead of print