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CURATOR
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Master of Science student at Dalhousie University's Medical Neuroscience department.

I'm interested in human anatomy and enjoy a special focus on retinal circuitry and function.

PINBOARD SUMMARY

Photoswitches: chemicals which respond to light enable visual responses in damaged retinas.

In 10 Seconds? Photoswitches are synthetic light-sensitive chemicals designed to restore vision in damaged eyes. The retina is the light-sensitive portion of our eye, a protrusion of the brain which houses a network of neurons. Here, photoswitches act on retinal neurons which normally don’t respond to light, to make them light-sensitive, creating new means for vision. Evidence is accumulating to support their use in clinical trials to treat vision loss.

What causes vision loss, anyway? Damage can result from diseases like retinitis pigmentosa which causes the loss of light-sensitive rods and cones (rod- and cone-shaped neurons, respectively) in our retina. Rods and cones are the front line responders to light, and as “photoreceptors” they convert light into electrical signals which are then passed further down the network of retinal neurons. With photoreceptor loss, there is a decreased amount of light-sensitivity in the retina, deteriorating vision.

How do photoswitches work? Photoswitch compounds can be safely injected into eyes to become become incorporated into retinal neurons. By pairing with proteins which control electrical signals, photoswitches can convert light into electrical activity. Early photoswitches activated retinal ganglion cells, the final cells in the network of retinal neurons, which forward visual information on to the brain. This bypassed the damaged rod and cone pathway to restore vision in mice. Cool! But, activating the last cell in the retinal network does not capture the full extent of retinal processing that would normally take place.

New photoswitches to turn on the light? Recently, (diethylamino-azo-diethylamino) DAD photoswitches have improved on initial counterparts. Their structure promotes the ease of their transport to become incorporated in neurons upstream of retinal ganglion cells like “bipolar" cells. This means that bipolar cell photoswitch-induced activity can flow through more of the retinal network before being sent off to the brain, benefitting from more “natural” visual processing.

So, can we use this to restore vision in humans? Clinical trials are still a few steps away but many groups show evidence that visual function, and not just light sensitivity, is a clinical inevitability with the use of photoswitches. As of now, the biggest step forward in clinical trials has used the incorporation of different light-sensitive compounds called “channelrhodopsins” but is still in early days.

11 ITEMS PINNED

Proceedings of the First International Optogenetic Therapies for Vision Symposium.

Abstract: Optogenetics is a research field that uses gene therapy to deliver a gene encoding a light-activated protein to cells providing light-regulated control of targeted cell pathways. The technology is a popular tool in many fields of neuroscience, used to transiently switch cells on and off, for example, to map neural circuits. In inherited retinal degenerative diseases, where loss of vision results from the loss of photoreceptors, optogenetics can be applied to either augment the function of surviving photoreceptors or confer light sensitivity to naturally nonlight sensitive retinal cells, such as a bipolar cells. This can be achieved either by the light sensitive protein integrating with native internal signaling pathways, or by using a dual function membrane protein that integrates light signaling with an ion channel or pump activity. Exposing treated cells to light of the correct wavelength activates the protein, resulting in cellular depolarization or hyperpolarization that triggers neurological signaling to the visual cortex. While there is a lot of interest in optogenetics as a pan-disease clinical treatment for end-stage application in the inherited degenerative diseases of the retina, research to date has been limited to nonhuman clinical studies. To address the clinical translational needs of this technology, the Foundation Fighting Blindness and Massachusetts Eye and Ear Infirmary cohosted an International Optogenetic Therapies for Vision Workshop, which was held at Massachusetts Eye and Ear Infirmary, Boston, Massachusetts on June 1, 2012.

Pub.: 19 Dec '13, Pinned: 17 Jul '17

Retinal implants: a systematic review.

Abstract: Retinal implants present an innovative way of restoring sight in degenerative retinal diseases. Previous reviews of research progress were written by groups developing their own devices. This systematic review objectively compares selected models by examining publications describing five representative retinal prostheses: Argus II, Boston Retinal Implant Project, Epi-Ret 3, Intelligent Medical Implants (IMI) and Alpha-IMS (Retina Implant AG). Publications were analysed using three criteria for interim success: clinical availability, vision restoration potential and long-term biocompatibility. Clinical availability: Argus II is the only device with FDA approval. Argus II and Alpha-IMS have both received the European CE Marking. All others are in clinical trials, except the Boston Retinal Implant, which is in animal studies. Vision restoration: resolution theoretically correlates with electrode number. Among devices with external cameras, the Boston Retinal Implant leads with 100 electrodes, followed by Argus II with 60 electrodes and visual acuity of 20/1262. Instead of an external camera, Alpha-IMS uses a photodiode system dependent on natural eye movements and can deliver visual acuity up to 20/546. Long-term compatibility: IMI offers iterative learning; Epi-Ret 3 is a fully intraocular device; Alpha-IMS uses intraocular photosensitive elements. Merging the results of these three criteria, Alpha-IMS is the most likely to achieve long-term success decades later, beyond current clinical availability.

Pub.: 10 Jan '14, Pinned: 17 Jul '17

Controlled release of photoswitch drugs by degradable polymer microspheres.

Abstract: QAQ (quaternary ammonium-azobenzene-quaternary ammonium) and DENAQ (diethylamine-azobenzene-quaternary ammonium) are synthetic photoswitch compounds that change conformation in response to light, altering current flow through voltage-gated ion channels in neurons. These compounds are drug candidates for restoring light sensitivity in degenerative blinding diseases, such as age-related macular degeneration (AMD).However, these photoswitch compounds are cleared from the eye within several days, they must be administered through repeated intravitreal injections. Therefore, we are investigating local, sustained delivery formulations to constantly replenish these molecules and have the potential to restore sight.Here, we encapsulate QAQ and DENAQ into several molecular weights of poly(lactic-co-glycolic) acid (PLGA) through an emulsion technique to assess the viability of delivering the compounds in their therapeutic window over many weeks. We characterize the loading efficiency, release profile and bioactivity of the compounds after encapsulation.A very small burst release was observed for all of the formulations with the majority being delivered over the following two months. The lowest molecular weight PLGA led to the highest loading and most linear delivery for both QAQ and DENAQ. Bioactivity was retained for both compounds across the polymers.These results present encapsulation into polymers by emulsion as a viable option for controlled release of QAQ and DENAQ.

Pub.: 11 Oct '15, Pinned: 17 Jul '17

Retinal prosthetics, optogenetics, and chemical photoswitches.

Abstract: Three technologies have emerged as therapies to restore light sensing to profoundly blind patients suffering from late-stage retinal degenerations: (1) retinal prosthetics, (2) optogenetics, and (3) chemical photoswitches. Prosthetics are the most mature and the only approach in clinical practice. Prosthetic implants require complex surgical intervention and provide only limited visual resolution but can potentially restore navigational ability to many blind patients. Optogenetics uses viral delivery of type 1 opsin genes from prokaryotes or eukaryote algae to restore light responses in survivor neurons. Targeting and expression remain major problems, but are potentially soluble. Importantly, optogenetics could provide the ultimate in high-resolution vision due to the long persistence of gene expression achieved in animal models. Nevertheless, optogenetics remains challenging to implement in human eyes with large volumes, complex disease progression, and physical barriers to viral penetration. Now, a new generation of photochromic ligands or chemical photoswitches (azobenzene-quaternary ammonium derivatives) can be injected into a degenerated mouse eye and, in minutes to hours, activate light responses in neurons. These photoswitches offer the potential for rapidly and reversibly screening the vision restoration expected in an individual patient. Chemical photoswitch variants that persist in the cell membrane could make them a simple therapy of choice, with resolution and sensitivity equivalent to optogenetics approaches. A major complexity in treating retinal degenerations is retinal remodeling: pathologic network rewiring, molecular reprogramming, and cell death that compromise signaling in the surviving retina. Remodeling forces a choice between upstream and downstream targeting, each engaging different benefits and defects. Prosthetics and optogenetics can be implemented in either mode, but the use of chemical photoswitches is currently limited to downstream implementations. Even so, given the high density of human foveal ganglion cells, the ultimate chemical photoswitch treatment could deliver cost-effective, high-resolution vision for the blind.

Pub.: 05 Aug '14, Pinned: 17 Jul '17

Photochemical approaches to vision restoration.

Abstract: Photoswitches are traditional pharmacologic agonists, antagonists, or channel blockers that are covalently modified with an azobenzene derivative. Azobenzene undergoes wavelength-dependent isomerization between cis and trans conformation. For some photoswitches, only one of these configurations is biologically active, resulting in light-dependent activation or inhibition of function. Photoswitches that feature a quaternary ammonium coupled to the azobenzene moiety cause light-dependent neuronal depolarization due to blockage of voltage-gated potassium channels. Two photoswitch strategies have been pursued. In the one-component strategy, the photoswitch is applied to native receptors; in the two-component strategy, the photoswitch is combined with virally-mediated expression of a genetically modified receptor, to which the photoswitch may covalently bind. The former approach is simpler but the latter allows precise anatomic targeting of photoswitch activity. Acrylamide-azobenzene-quaternary ammonium (AAQ) is the prototypical first-generation one-component photoswitch. When applied to retinas with outer retinal degeneration, ganglion cell firing occurs in response to blue light, and is abrogated by green light. In vivo, AAQ restored pupillary light responses and behavioral light responses in blind animals. DENAQ is a prototypical second generation one-component photoswitch. It features spontaneous thermal relaxation so cell firing ceases in dark, and features a red-shifted activation spectrum. Interestingly, DENAQ only photoswitches in retinas with outer retinal degeneration. MAG is a photoswitched glutamate analog which covalently binds to a modified ionotropic glutamate receptor, LiGluR. When applied together, MAG and LiGluR also rescue physiologic and behavioral light responses in blind mice. Together, photoswitch compounds offer a potentially useful approach to restoration of vision in outer retinal degeneration.

Pub.: 15 Feb '15, Pinned: 17 Jul '17

Flipping the Photoswitch: Ion Channels Under Light Control.

Abstract: Nature has incorporated small photochromic molecules, colloquially termed 'photoswitches', in photoreceptor proteins to sense optical cues in phototaxis and vision. While Nature's ability to employ light-responsive functionalities has long been recognized, it was not until recently that scientists designed, synthesized and applied synthetic photochromes to manipulate many of which open rapidly and locally in their native cell types, biological processes with the temporal and spatial resolution of light. Ion channels in particular have come to the forefront of proteins that can be put under the designer control of synthetic photochromes. Photochromic ion channel controllers are comprised of three classes, photochromic soluble ligands (PCLs), photochromic tethered ligands (PTLs) and photochromic crosslinkers (PXs), and in each class ion channel functionality is controlled through reversible changes in photochrome structure. By acting as light-dependent ion channel agonists, antagonist or modulators, photochromic controllers effectively converted a wide range of ion channels, including voltage-gated ion channels, 'leak channels', tri-, tetra- and pentameric ligand-gated ion channels, and temperature-sensitive ion channels, into man-made photoreceptors. Control by photochromes can be reversible, unlike in the case of 'caged' compounds, and non-invasive with high spatial precision, unlike pharmacology and electrical manipulation. Here, we introduce design principles of emerging photochromic molecules that act on ion channels and discuss the impact that these molecules are beginning to have on ion channel biophysics and neuronal physiology.

Pub.: 19 Sep '15, Pinned: 17 Jul '17