Human stem cell-derived retinal cells show promise as treatment for macular diseases

Note: The post below is  from the study (pdf) published in The Lancet.

Since 1981, when pluripotential cell cultures were first derived by Evans and Kauffman, embryonic stem cells (ESC) have been regarded as a potential source of therapeutic cells for a wide range of diseases caused by tissue loss or dysfunction. Despite the great therapeutic potential, their plasticity and unlimited capacity for self-renewal raise concerns about serious safety issues, including the ability to form teratomas and other tumours, potential immune reactions, and the risk of differentiating into unwanted cell types. 

DENAQ, a new chemical that may restore sight in retinitis pigmentosa and macular degeneration

Scientists from the University of California, Berkeley report on a chemical ‘photoswitch’ named DENAQ that may be a potential drug for treating patients suffering from blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD).

RP and AMD are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. In the paper published in Neuron, the authors led by Dr Richard H Kramer report about a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight, compared to earlier attempts at photoswitch that required very bright ultraviolet light, making it unsuitable for use in patients. In experiments conducted on three-month to six-month-old healthy mice, and on mice carrying a mutation causing nearly all their rods and cones to degenerate by the time they were a month old, a single intraocular injection of DENAQ has been able to photosensitize the blind retina for about 3 days, restoring electrophysiological and behavioral responses with no toxicity. DENAQ also is able to rapidly turns itself off, allowing rapid repeated stimulation of the retina. The researchers compared the retinae of DENAQ-injected mice to untreated healthy mice and found no signs of toxicity for up to 30 days after the injection.

Retinas with damaged rods and cones are subject to several morphological and biochemical changes, making them different from a healthy retina in more than one way. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated or dead photoreceptors. Apparently, the degenerated outer retinal cells help in DENAQ photosensitization due to changes in electrophysiological characteristics, while the presence of intact photoreceptors possibly prevent this action. This appears to give it significant advantage, since this selective action on diseased tissue alone may potentially reduce side effects on healthy retina.

DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.

The researchers plan on conducting more experiments, including in larger animals before its safety can be established and any clinical trials can be considered.

To watch a video of Dr Kramer explaining his work, click here.

Sources: Neuron, Univ of California, Berkeley, Kramer Lab, The Scientist

Editor's note: The drug appears to have an exciting potential to help patients with retinitis pigmentosa and age-related macular degeneration. There are two thoughts though. 

1. Such a drug may only work in advanced stages of the disease, considering we will have to wait for the retinal cells to die before it can act.

2. We also need to know how long the effect of one injection lasts. Such treatment may require repeat injections over a long-term, something similar to Lucentis or Avastin.

Researchers find novel pathway that helps eyes quickly adapt to darkness

It's almost time for the movie to start. As you hurry from the lobby into the darkened theater, you may have to stop, as the transition from light into darkness renders you temporarily blind. Cells in the eye's retina must adapt before you can begin to distinguish heads from backs of chairs. As the cells adjust, sight will be restored enough to avoid tripping over a chair, or sitting in a stranger's lap!

Scientists have long known that these cells, called photoreceptors, are involved in this adaptive process, but a study from investigators at Washington University School of Medicine in St. Louis and Boston University School of Medicine has uncovered a new pathway in the retina that allows photoreceptor cells to adapt following changes in light exposure.

The discovery could help scientists better understand human diseases that affect the retina, including age-related macular degeneration, the leading cause of blindness in people over the age of 50. That's because the process of adapting to darkness involves the same cells that are affected in macular degeneration and other blinding retinal diseases.

The findings are reported online in the journal Nature Neuroscience and will be the cover story in the March print edition.

The retina's two main light-sensing cells are the rods and cones. Both use similar mechanisms to convert light into vision, but they function differently. Rods are highly sensitive and work well in dim light, but they can quickly saturate with light and stop responding. They don't sense color either, which is why we rarely see colors in dim light.

Cones, on the other hand, allow us to see colors and can adapt quickly to stark changes in light intensity. The research team focused on cone cells, studying their ability to continue functioning in very bright light and to adapt quickly when that light is shut off.

"Rods can take up to an hour to adapt to darkness," says principal investigator Vladimir J. Kefalov, Ph.D., Assistant Professor of Ophthalmology and Visual Sciences. "Cones, by contrast, adapt in three to five minutes."

Scientists have known for years that light-sensing molecules bind together to make up visual pigments. Those pigments are destroyed when they absorb light and must be rebuilt, or recycled, for the cone cells to continue sensing light. In order to be recycled, key components of pigments called chromophores leave the retina, and travel to the eye's retinal pigment epithelium where the chromophore is restored and returned to the retina.

"If the chromophores cannot be recycled, cone cells gradually run out of visual pigment and can't detect light," Kefalov says.

But the process of traveling to and from the pigment epithelium takes too long to explain how cones quickly adapt to darkness following exposure to bright light, so Kevalov's team went looking for a second, supplementary pathway.

Working in salamander eyes, the research team removed the pigment epithelium layer so that pigment molecules could not be recycled using the known pathway. When the scientists exposed the retina to bright light and then to darkness, the cones continued to function, even without the pigment epithelium. That meant the pigment molecules were recycled in spite of the fact that they could not travel to the pigment epithelium.

"So it was clear that a second pathway is being used by the cone cells," Kefalov says.

But where? Biochemical evidence had suggested cells called Müller cells might be involved. Like glial cells in the brain that support and interact with neurons, Müller cells in the retina support and interact with photoreceptors. The researchers treated salamander retinas with a chemical that destroyed the Müller cells.

They repeated the experiment exposing the retina to bright light, followed by darkness. "And by blocking the function of Müller cells, we prevented the recycling of chromophores. The cones ran out of photopigment and could not adapt to dark," Kefalov says.

The group then conducted the same series of experiments in the mouse retina, with the same results, suggesting the second pathway involving Müller cells also is important in the mammalian eye. If it is active in the human eye, Kefalov believes it may be possible one day to manipulate this pathway to improve vision when the other one involving pigment epithelium has been interrupted by injury or disease.

One such disease is age-related macular degeneration, where cone cells begin to malfunction over time. Because the disease and the pathway Kefalov's team identified both involve cones, he says it may be possible someday to target that pathway, rev up its activity and supplement or rescue the function of cones.

Before that happens, he says it will be important to figure out exactly how the Müller cells are interacting with photoreceptors. Although these studies confirmed the existence of the second photoreceptor pathway, they didn't reveal how it works. Kefalov's laboratory has recently received a five-year, $1.9 million National Eye Institute grant to study how this newly identified visual pathway functions in the retina.

If you wish to reacd this paper, please click here.

News from the website of Washington University in St. Louis.