Proyectos Científicos

Good Cholesterol Gene Linked to AMD Control

It may come as no surprise to learn that vision scientists are pursuing a genetic connection between age-related macular degeneration (AMD) and high density lipoproteins (HDLs). HDL is commonly known as good cholesterol. HDLs transport cholesterol and other fats through the bloodstream. A common belief is that early AMD is associated with an accumulation in the retinal pigment epithelium (RPE) of oxidation products of cholesterol that form drusen. Drusen are tiny accumulations of extracellular material that can grow and interfere with normal structure and function of the macula, leading to AMD.

Johanna M. Seddon and her colleagues examined several thousand people (some with and some without AMD) and discovered, based on genome-wide association studies, an association between AMD and a variant in the hepatic lipase gene (LIPC), an important enzyme in the HDL biochemical pathway.  They found that the same LIPC gene variant that increases serum levels of HDL also appears to decrease the risk of AMD, which could affect drusen formation and reduce the risk of AMD. This gene is newly associated with AMD and may lead to new therapeutic approaches for preventing a treating the disorder.

(J.M. Seddon, R. Reynolds, J. Fagerness, L. Sobrin, E.H. Souied, P. Bernstein, M. Brantley, Jr., N. Katsanis, R. Allikmets, M. Daly)

 

 

Optogenetics for Re-activating Cone Photoreceptors in RP

 

Optogenetics is so new a field that many scientists are still learning what it means and how it works. Brain scientists are a little ahead. They have begun applying it to animal models of depression, narcolepsy, schizophrenia, autism, Parkinson’s disease, addiction, and memory. Optogenetics is a technology for controlling the “on-off” of neurons; in other words, for triggering or quelling action potentials within groups of nerve cells or in individual nerve cells. It uses a combination of light sensitive proteins (opsins) and pulses of light of different wavelengths to trigger or depress depolarization of nerve cells.

 

Optogenetics was pioneered and named by Karl Deisseroth, a psychiatrist and optical neuroengineer at Stanford University.  (See Deisseroth K, Feng G, Majewska AK, Miesenböck G, Ting A, Schnitzer MJ. (2006) “Next-generation optical technologies for illuminating genetically targeted brain circuits.”  J. Neurosci. 26(41):10380-6.)

 

At ARVO 2010, Swiss, Germany, and French collaborators reported on how they are applying optogenetics to cone photoreceptors in mouse models of retinitis pigmentosa and activating retinal circuit functions.

 

First, they showed that by using adeno-associated gene transfer techniques they could successfully elicit expression of channelrhodopsin in cone cells. (The opsins embed in nerve cell body membranes where they act as gatekeepers to ion flow.) Next, the researchers showed that by stimulating these opsins with red light they could trigger a hyperpolization of the cone cells, thereby demonstrating a restoration of light sensitivity. Furthermore, this cone sensitivity subsequently produced spiking activity in retinal ganglion cells, a response in the brain’s visual cortex, and optomotor behavioral changes in treated animals.

 

The researchers are studying how optogenetics can ultimately be applied to technologies for aiding people with RP, perhaps using special eyeglasses with light emitting sensors for turning cones cells on and off.

 

(D. Balya, V. Busskamp, J. Duebel, M.W. Seelinger, M. Biel, K. Deisse4roth, J.A. Sahel, S.A. Picaud, B. Roska)

 

(Other researchers are also examining different wavelengths of light for modulating neural firing. Still others are looking at the restored papillary response created by this approach, which could signal an effect on circadian rhythms. )

 

AMD Severity and Dietary Characteristics

Researchers involved in the Age-Related Eye Disease Study 2 (AREDS2) described dietary characteristics of over 4000 study participants and compared these factors to severity of disease. They evaluated patient-reported dietary intake of lutein/zeaxanthin, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Analysis of the results show that intake of DHA and EPA is inversely related to AMD severity. In other words, the higher the intake of these compounds, the lower the score on tests of AMD severity related to drusen and pigment characteristics of the macula.

 

(J.R. Chang, T. Clemons, J.P. SanGiovanni, E. Agron, E. Chew)

New Results from the Subretinal Electronic Implant Study in Tuebingen, Germany

 

In a pilot study, performed by Retina Implant AG at the Tuebingen University Center for Ophthalmology, 11 patients  received a subretinal microphotodiode array with 1500 light sensitive photodiodes, amplifiers and electrodes, demonstrating unique visual results.  The implant provides a visual field of approximately 11 by 11 degrees and sends an image with 1500 pixel seven times per second via inner retinal neurons to the brain. No major adverse events related to the implant were observed. Some patients were able to recognize letters of 4 cm size at arm’s length, one patient named unknown objects, such as banana, knife, fork, spoon and pointed exactly to the localization of such objects, differentiated 7 shades of grey and localized persons in the room. One patient reported that he can see the letters as he has learned them in school without scanning them.  As the subretinal light sensitive chip moves exactly with the eye, no cameras outside the body are necessary; continuous head-shaking to constantly refresh the image can be avoided. Importantly, it was found that the Tuebingen subretinal electronic implants provide continuous, stable percepts in blind subjects as the image receiver is directly linked to eye movement. The researchers consider the results with their high resolution implant as first proof of concept that patients can regain really useful vision by subretinal electronic implants.

In additional studies it was found that explantation of the active subretinal device through a transscleral approach  was possible and uneventful. Only minor tissue reactions were observed. This makes possible the re-implantation of similar devices in the same retinal region.

It was reported that Retina Implant AG has meanwhile started a new multicenter study including centers in England, Italy, Hungary and Germany.

 

(E. Zrenner, H. Sachs, F. Gekeler, K.U. Bartz-Schmidt, Besch, H. Benav, A. Bruckmann, A. Kusnyerik, A. Stett, K. Stingl, R. Wilke)

Second Sight® ArgusTM II Retinal Prosthesis Study: Interim Results

 

The company Second Sight® reported at ARVO 2010 on performance results from its Argus II Retinal Prosthesis Study involving 32 patients with late-stage retinitis pigmentosa. All participants had bare light perception or worse at the start of the study. Each had placed on his or her retina a 60-electrode grid designed to respond to electrical pulses triggered by images captured and transmitted by an eyeglass-mounted video camera. The idea is that the retina will respond to the electrical impulse by sending a signal of its own that will travel along the optic nerve to the brain and be interpreted as a shape in the visual field.

 

Tests of the Argus II system were based on participants’ ability to determination the direction of motion of a line, the location of a square, the identity of letters and utensils, and to follow a line towards a door. All were in high contrast against their background. All 32 participants, from the U.S., Mexico, and Europe, had practiced with the system in their homes where they reported being able to detect phosphenes (light flashes without light actually entering the eye). Use ranged from four months to a little over three years.

In finding the door, participants did better when the device was on than off. The majority also did better in detecting the square with the device on. Direction of motion and ability to identify letters and utensils were likewise improved.

 

Second Sight® is submitting an application for CE mark certification in Europe.

(M.S. Humayun, L. da Cruz, G. Dagnelie, S. Mohand-Said, P. Stanga, R.N. Agrawal, R.J. Greenberg. A.Sahel)

(The researchers also described safety tests showing no harmful effects in the treated compared to the untreated eye. In addition, they report an ability to work much faster to identify shapes—even complicated shapes—using the Argus II retinal prosthesis.  Participants with the best outcomes could read letters of varying size and in various colors.  The researchers consider their results to represent a milestone in artificial vision. Other groups are pursuing other forms of retinal stimulation and placement of devices at different positions above and below the retinal surface. )

 

FDA Grants Fast Track Designation for Dry AMD treatment

The U.S. Food and Drug Administration has granted fast track designation for the testing of a novel therapy developed by Acucela Inc. and Otsuka Pharmaceutical Co. Ltd. for treating dry age-related macular degeneration (dry AMD). There has been no successful treatment to date. The investigational drug, called ACU-4429, is a visual cycle modulator designed to prevent production of toxic by-products of the visual cycle that can lead to dry AMD. ACU-4429 works by slowing metabolism of rod photoreceptor cells, thereby decreasing lipofuscin accumulation in the retinal pigment epithelium. Lipofuscin accumulation is a precursor to dry AMD. ACU-4429 is given as a daily pill. This is in contrast to several compounds for wet AMD drugs that are administered by intravitreal injection.

 

Measurements for detecting retinal disease progression

Researchers are looking at ways to draw a correlation between the appearance of the retina in various retinal disorders and the functioning of the retina. For example, in a study using spectral domain optical coherence (SD-OCT), fundus autofluouresence (AF) imaging, and microperimetry—in patients with autosomal dominant RP, autosomal recessive RP, or Usher syndrome—researchers found a correlation between retinal thickness and retinal function, and between a hyperautofluorescent ring in the retina and a zone of abnormal retinal morphology and function.  They found the ring measurements to be a clinically significant test for assessing the progression of certain retinal disorders and that it may be a useful indicator for determining effects of treatment.

 

(E. Lanassi, M. Hawlina)