Proyectos Científicos

Estudio sobre la prevalencia de las enfermedades distróficas de la retina , PREVARET

Las enfermedades distróficas de la retina constituyen un grupo de patologías muy diversas, de baja incidencia y en muchos casos de difícil diagnóstico. A esto se une que no existe una fuente que haya coordinado y centralizado datos reales y fiables sobre dichas enfermedades, y que no se dispone de centros de referencia oficiales, la capacidad de realización de estudios epidemiológicos es muy limitada.

Por este motivo la Fundación Retina España, se había propuesto peomover una base de datos en la que poder cuantificar a los afectados por enfermedades distróficas de la retina. El proyecto PREVARET pretende realizar un estudio epidemiológico que permita obtener una primera  estimación del número de personas afectadas por algún tipo de enfermedad distrófica de la retina.

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Estudio Epidemiológico sobre las Enfermedades
Heredo Distróficas de la Retina

investigacion social

Proyecto aprobado por el Comité Ético de Investigación Clínica

Regional de la Comunidad de Madrid el 15 de abril de 2010


1. ¿Qué es Prevaret?

Es un estudio que pretende realizar una estimación aproximada de la prevalencia de las enfermedades heredo distróficas de la retina tomando como base el diagnóstico clínico de las mismas y mediante una recogida prospectiva de casos, en cinco áreas de estudio en la comunidad de Madrid. Se evaluarán específicamente dos variables de tipo sociológico que pueden impactar en la cifra estimada de prevalencia: la renta per capita y la densidad de población.

Se   trata,  en   definitiva,   de  un  proyecto   prospectivo  cuya  duración   inicial estimamos   en dos  años (2010 y 2011).


2. ¿Por qué Prevaret?

No se conoce la prevalencia de las Enfermedades heredo distróficas de la retina. Ante esta situación la Fundación Retina España ha promovido la realización de este estudio piloto como una primera aproximación que ofrecerá al menos una cifra de prevalencia de los pacientes que acuden a su hospital de referencia.


3.-Objetivos


Objetivo principal

Estimar la prevalencia en los años 2010 y 2011 de las enfermedades distróficas hereditarias de la retina (EDR) dentro de la población censada en varios distritos sanitarios pertenecientes a la Comunidad Autónoma de Madrid (áreas de estudio) que acude al Hospital de referencia.


Objetivo secundario

Evaluar las diferencias en la prevalencia de las ERD que se distribuyen según cinco áreas de estudio escogidas en la Comunidad de Madrid,  en base a su densidad de población y renta per cápita (como indicador de diferencias socioeconómicas).


4. Finalidad

Los resultados de este proyecto beneficiarán directamente a los propios afectados por enfermedades distróficas de la retina y sus familiares.

Además, desde una perspectiva sociológica, el proyecto beneficia a la sociedad en su conjunto, pues se podrán elaborar conclusiones valiosas sobre estas patologías, no sólo pensando en los aspectos meramente científicos, sino también en la problemática social.

Finalmente, dimensionar la realidad sociosanitaria de estas patologías servirá para implementar políticas ajustadas a las necesidades reales del colectivo afectado.


5.- Centros implicados

-        Hospital Universitario de la Paz

-        Hospital Universitario de Getafe

-        Hospital  Universitario Puerta de Hierro

-        Hospital Infanta Sofía

-        Hospital Infanta Cristina

-        Consejería de Sanidad de la Comunidad de Madrid

-          Servicio Madrileño de la Salud (SERMAS)

http://www.madrid.org/cs/Satellite?pagename=HospitalGetafe/Page/HGET_home

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)

 

 

 

 

 

Nanoparticle cDNA Delivery In Animal Models of Retinal Dystrophies

 

Compacted DNA (cDNA) nanoparticles are being tested as vehicles for transferring genes into cells of the eye. In this compacted form, the DNA can enter the nuclear membrane of cells, where it must be delivered to be effective.  Nanoparticle delivery is being researched as an alternative to virus-mediated gene delivery.

 

Following injection of the nanoparticles into the eye, gene expression has been documented in photoreceptors, retinal pigment epithelial cells, retinal ganglion cells, and in other cells of the eye. Researchers have now shown that the nanoparticles can be targeted to specific locations by controlling the injection site (e.g., subretinal, intravitreal) and that gene expression levels are dose-dependent and sustained. In animal models of inherited retinal dystrophies, subretinal injections transfected most photoreceptors and produced nearly normal levels of gene expression. This produced significant improvements in photoreceptor function and structure and restoration of retinal phenotype. No toxicity was associated with the treatment which makes it promising as a safe non-viral delivery mechanism for supplying therapeutic genes to the retina and other tissues of the eye.

 

(M.I. Naash)

Light-stimulated LiGluR Drives Visual Response in Retinal Ganglion Cells in RP Mice

Along these same lines was a report by John Flannery and colleagues who used an adeno-associated virus (AAV2) to deliver the engineered light-activated glutamate receptor (LiGluR) to the retinal in several different mouse models of retinitis pigmentosa. LiGluR successfully integrated into retinal ganglion cell membranes and, when prompted by light of various wavelengths, responded by opening ion channels, which triggered action potentials. This technique is promising for retinal conditions where photoreceptors cells are damaged or degenerated but retinal ganglion cells remain intact. The researchers further demonstrated that the depolarization started by the light stimulation was propagated along the visual pathway to the visual cortex. One of the beauties of this optogenetics approach is that light is non-invasive. The technique requires no implanted electrodes or other devices. The light can be projected onto discrete or diffuse regions of the retina and at various depths to produce responses that will hopefully result in recognizable visual patterns in humans with late stage retinal degeneration.

(N. Caporale, K.D. Kolstad, I. Tochitsky, D. Dalkara, T. Huang, D. Trauner, R.H. Kramer, Y. Dan, E.Y. Isacoff, J.G. Flannery)

 

Increased Macular Thickness in CNTF Therapy Attributed to ONL

Weng Tao and her colleagues reported at ARVO 2010 their additional findings about the encapsulated cell technology (ECT) intraocular implant containing genetically modified cells that secrete ciliary neurotrophic factor (CNTF). The implant releases CNTF in a sustained fashion. The hope is that it will protect photoreceptor cells in patients with retinal degenerative disorders. CNTF is being tested in clinical trials in patients with retinitis pigmentosa and has demonstrated a positive biological effect.

 

One of the effects of CNTF is a dose-dependent, statistically significant increase in macular thickness involving the photoreceptor cell layer. In the current report, the researchers reported on their use of Fourier domain (fd)OCT to investigate the source of the thickening. (fd)OCT, compared to other OCT technologies, greatly enhances depth resolution in tissues and increases the detail scientists can see and the measurements they can make of the retina. Their results showed that the thickness is due primarily to a difference in the width of the outer nuclear layer (ONL). The ONL is composed of the cell bodies of the rods and cones. The thickening could represent increased transcriptional and metabolic activity of the cells. Whether it presages functional improvement is yet to be determined.

 

The next step for the scientists is a Phase II efficacy study in RP patients to determine whether CNTF can slow degeneration of cells and increase visual activity.

(D.G. Birch, K.G. Locke, H. Patel, W. Tao)

 

Gene Therapy Clinical Trial Aims to Identify a Subset of LHON Patients and Carriers

 

Researchers at ARVO 2010 reported on enrollment (n=46) in a gene therapy clinical trial involving Leber hereditary optic neuropathy (LHON) patients. The ultimate goal of the research is to improve visual function by replacing a mutated gene in retinal ganglion cell mitochondrial DNA (mtDNA).

 

LHON was the first neurodegenerative disease for which a mitochondrial pattern of inheritance was described. It follows a maternal inheritance pattern and is characterized by retinal ganglion cell degeneration, retinal nerve fiber degeneration, and vision loss. Three primary mutations (at nucleotide pair 3460, 11778, and 14484) are generally agreed to be the primary causes of most cases of LHON.  The scientists are studying carriers and patients with the G1178A mutation. The G1178A mutation results in an amino acid substitution in the ND4 gene product. There is currently no treatment for LHON.

 

The mitochondrial ND4 gene provides instructions for making a protein called NADH dehydrogenase 4. The protein is part of an enzyme complex involved in energy production. The goal of treatment is to rescue retinal ganglion cells using AAV-mediated intravitreal delivery of a normal ND4 gene.

 

(B.L. Lam, W.J. Feuer, V. Porciatti, F. Abukhalil, A. Morante, J.R. Guy)

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Stem Cells for Replacing Damaged Retinal Cells

 

Stem cells are pluripotent, meaning that they are capable of differentiating into a variety of cells types. They exist as embryonic stem (ES) cells or as induced pluripotent stem (iPS) cells. The later are produced from mature cells. Stem cell therapy is being studied as a means for replacing damaged retinal cells. In fact, it was recently demonstrated that adult somatic (e.g., skin) cells can be persuaded (in vitro) to form stem cells that are capable of becoming cells of the eye. This remarkable finding raises the possibility of generating new tissue from mature cells of people who have retinal disease to serve as pluripotent cells that could be grafted into the eyes to take on characteristics of normal vision cells. Every year at the ARVO annual meeting certain topics generate a buzz. Stem cell research and stem cell-based treatments received a lot of attention this year.

 

Several laboratories have developed protocols for forming retinal cells from ES and iPS cells and have shown that, in animals with retinal degenerative disease, retinal cells derived from both can become part of the retina.

 

In the U.S., stem cell-based products intended for patient administration are regulated by the FDA Center for Biologics Evaluation and Research. The FDA considers factors such as the viability of the stem cells transplant, migration of cells from the site of delivery, further differentiation and proliferation of the stem cells to other phenotypes and possible tumorgenicity, and functional physiologic integration of the cells. Stem cell research is young and, before being applied to humans, needs to be studied thoroughly for safety and therapeutic efficacy.

(T.A. Reh; K. Wallace, D.O. Clegg, M. Friedlander, D.W. Fink)

EYS Mutations in RP Patients in France

Scientists studying RP in French patients believe that mutations in the EYS gene are a major cause of retinitis pigmentosa (RP) in France and probably elsewhere. The EYS gene is the largest known gene in the human eye, spanning over two megabits. The researchers found 37 likely mutations in the EYS gene among more than 200 people with sporadic or autosomal recessive retinitis pigmentosa for whom known mutations had previously been ruled out. Some patients had a single mutation while others had several. Most patients had classical signs of RP and a typical course of relatively preserved central vision until late in the disorder. This prevalence of EYS gene mutations in this population suggests a prominent role in other cases of RP.

(I.S. Audo, J.-A. Sahel, S. Mohand-Saïd, M.-E. Lancelot, I. Barragan, M.M. Abd El-Aziz, E.F. Nandrot, G. Antinolo, S.S. Bhattacharya, C. Zeitz)

(Other researchers recently reported a high prevalence of EYS mutations in Israeli and Palestinian families who have autosomal recessive RP.  The researchers are D. Bandah-Rozenfeld, K.W. Littink, T. Ben-Yosef, T.M. Strom, I. Chowers, R.W. Collin, A.I. den Hollander, I. van den Born, M.N. Zonneveld, S. Merin, E. Banin, F.P. Cremers, and D. Sharon. Their report was published online ahead of print April 7, 2010; IOVS. doi:10.1167/iovs.09-4732.)

Adeno-associated Virus (AAV)-Mediated RPE65 Gene Replacement Trials in Humans with LCA

 

In humans, mutations in RPE65 can lead to Leber’s congenital amaurosis or retinitis pigmentosa.  In young adults with RPE65-associated Leber’s congenital amaurosis, subretinal injection of a RPE65 transgene has been shown to improve vision and retinal function. A new Phase 1 dose-escalation study of patients ranging in age from 8 to 44 shows the greatest improvements in the younger subjects.

 

(E.A. Pierce)

Inhibition of the Retinal Vasculature Endothelial Cell Tight Junctions to Provide Systemic Neuroprotective

 

Endothelial cells of the retinal microvasculature are bound to adjacent cells by “tight junctions” that prevent passage of potentially harmful substances from the blood into surrounding tissues. Unfortunately, this inner blood-retina barrier (IBRB) also thwarts transfer of potentially therapeutic drugs. Researchers report that they have been able to breach the endothelial barrier and administer drug therapy, in preclinical models, by systemic administration of siRNA against claudin-5, a protein in the tight junctions, or by locally incorporating shRNA targeting claudin-5 into an inducible AAV-2/9 gene therapy vector system. (siRNAs and shRNAs disrupt gene expression.) The approaches have been effective in several animal models including the IMPDH1-/- mouse, a model of autosomal recessive retinitis pigmentosa.

 

(P. Humphries)

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