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What is LCA?
| 1. | Definition of LCA
Leber’s Congenital Amaurosis (LCA) is a rare, hereditary disorder that leads to retinal dysfunction and visual impairment at an early age – often from birth. Of all the retinal degenerations, LCA has the earliest age of onset and can be the most severe.
LCA bears the name of Dr. Theodore Leber who first described the condition. The term amaurosis refers to any condition of blindness or marked loss of vision, especially loss of vision in which there is little or no change in the appearance of the eye itself. LCA is sometimes confused with another condition termed Leber’s Hereditary Optic Neuropathy (LHON) that also leads to visual impairment. However, LCA is a separate and distinct disease.
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| 2. | LCA Phenotype
The clinical signs of a disease are collectively called the phenotype. Besides vision loss, other signs of LCA are nystagmus (roving eye), sluggish or nonexistent pupillary response and, in some cases, eye rubbing (oculo-digital reflex). In a smaller number of cases, there can be lens opacity (cataract), cornea abnormality (keratoconus), aversion to light (photophobia), hearing impairment and possibly developmental delays. Retinal blood vessels can become thin and narrow and there can be pigmentary changes that an Ophthalmologist can see within the eye.
A key feature of LCA is an abnormally low electrical response of the retina. This can be measured by the Ophthalmologist using a method called Electroretinography. In this procedure, the retina is stimulated by light and the electrical response pattern is recorded on an electroretinogram (ERG) and compared with ERG responses from normal subjects.
Some LCA types are progressive in that they become more severe with age and some are stationary in that there is little change noted with time.
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| 3. | LCA Genotype
In general, the term Genotype refers to the full genetic constitution of an individual. In a specific disease process, the “Disease Genotype” generally refers to the specific gene (or genes) whose mutation causes the disease. LCA can best be thought of as a grouping of hereditary diseases within a larger grouping of diseases called Retinitis Pigmentosa (RP). RP is a family of hereditary diseases of different causes whose common end point is retinal degeneration and loss of vision . Thus, LCA is just one special form of RP. This is an important concept, especially in considering treatments for LCA that may originally be designed for types of classical RP. It is estimated that forms of LCA comprise about 5% of all known hereditary retinal degenerations.
At present, 9 different gene mutations are known which lead to different forms of LCA. These are listed in Section 3 along with short descriptions.
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| 4. | Retinal Anatomy
The retina, as the brain, is part of the Central Nervous System. It is a thin, transparent tissue that is attached inside the back part of the eye. Its main function is to capture light images, begin their processing and pass them down the optic nerve to the brain. Structurally, the retina is stratified, i.e., most cells are in distinct bands or layers. In fact, one can think of the retina as a layer cake.
Following is a short description of the important cells types of the retina--
Photoreceptor Cells:
The most important cell is the photoreceptor neuron. Its main function is to capture the light energy in a visual image and convert it to an electrical response. This is done is a specialized part of the photoreceptor cells called the outer segment. In the outer segment is concentrated the visual proteins (pigments) like rhodopsin. These are the proteins that actually capture the light energy. Once the photoreceptor neuron converts the photic energy to an electrophysiological signal, it passes this signal on to secondary neurons in the next layer of the retina (e.g., bipolar cells) and ultimately to the brain.
There are two main types of photoreceptor cells in most animal retinas. These are called rods and cones. Rod cells are, as the name implies, rod-shaped. They are designed to mainly function in dim light and in peripheral vision. Cone cells are more cone shaped. They serve in central vision, bright-light vision and in color vision. There is a concentration of cone cells in a highly specialized, region of the retina called the macula. Most of our central and sharp vision uses macular cone cells.
Interestingly, the photoreceptor cells point towards the back of the eye, necessitating light to pass through all the other retinal layers before striking the photoreceptors.
Retinal Pigment Epithelium (RPE) Cells:
Juxtaposed to the layer of photoreceptor cells is a single cell layer of RPE cells. Perhaps, think of them as frosting on the retinal “cake”. They are tightly intertwined with the outer segments of the photoreceptor cells. The RPE cell layer functions in maintaining proper function of the photoreceptor cells which are thought to have the highest metabolic activity of any cell type in the human body. Thus, RPE cell bring nutrients and oxygen to photoreceptor cells and remove waste products. RPE cells also are heavily pigmented (melanin granules), allowing for capture of stray light. Last but not least, RPE cells are intrinsic to vision in that they participate in the visual cycle with photoreceptor cells. They store the vitamin A (retinoids) needed in vision and also contain enzymes that chemically alter vitamin A to forms used in photoreceptor outer segments in the visual process. When RPE cells are not functioning properly, photoreceptor cells are usually quickly affected resulting in retinal degeneration.
On the other side of the RPE cell layer from the photoreceptors is a dense network of blood vessels called the choroid. It is from this blood vessel system that RPE cells get the nutrients to pass on to photoreceptor cells.
Other Retinal Cell Types:
Beneath the photoreceptor cells are several stratified cell layers. Within these layers are secondary neurons such as bipolar cells, amacrine cells and ganglion cells. These cells are all connected through structures called synapses. The function of these cells is to begin the processing and integration of the visual signals. These signals are finally passed to the brain through the optic nerve. The optic nerve consists of many long, thin processes (axons) of ganglion cells.
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| 5. | Molecular Biology and Genetics Primer
To understand the hereditary nature of LCA and its causes, one has to understand the basic principles of how any trait, good or bad, is genetically passed on. All cells of the body have a central organelle called a nucleus. In the nucleus is a very long strand of genetic information called DNA. DNA is organized into coiled structures called chromosomes. Functionally, DNA is divided into specific areas - called Genes - which act as templates for individual proteins. It is estimated that humans have 30-70,000 separate genes encoded on their DNA – collectively called the human genome.
Genes:
To make a specific protein (e.g., one important in the visual process) within a cell, signals in the nucleus activate the gene. The gene functions as a bluepring, coding for a specific messenger molecule called messenger RNA (mRNA). This secondary blueprint moves out of the nucleus and ultimately directs the formation of the specific protein. Some genes are activated to only function at certain times of development or are specific to only certain cell types of the body. Hence, the opsin gene (visual protein) is present in the DNA of all cell types of our body but only will be activated to produce the opsin protein in photoreceptor cells of the retina.
Mutations:
As with all biological mechanisms, changes occur. Occasionally, the genetic building blocks of the DNA in the nucleus can be altered or mutated such that the basic blueprint is changed and thus the resultant protein is changed (mutated). Mutations can be good or bad. A mutation that allows for improved function of an important protein enzyme is probably good while a mutation that disables the enzyme could be very bad. Sometimes the mutation is so severe that the protein is not synthesized at all. In a hereditary disease like LCA, a DNA mutation can cause a protein that is important in the visual process to malfunction or not function at all, leading to visual impairment or blindness.
Hereditary Nature of LCA:
All forms of RP, including individual types of LCA are hereditary diseases, i.e., they are passed down through the generations within families. Hereditary diseases, in general, come in three major genetic modes of inheritance called dominant, recessive or X-linked. Most of the forms of LCA are inherited in a recessive manner although one form has a dominant mode of inheritance. Sometimes, people carry only one mutated gene, the other being normal. In the case of recessive genetic diseases, these people are called “carriers” since they carry the gene and can pass it on to their children but they themselves do not show the signs of the disease.
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| 6. | Gene Mutations that Cause LCA
To date, nine genes have been identified whose mutations lead to forms of LCA. Three other areas have been identified on human chromosomes in which an LCA gene resides but has not been specifically identified. Mutations in these genes do not always cause LCA. For example, mutations in some areas cause other retinal degenerations that have characteristics different from LCA. Investigators believe that not all LCA genes have been found and that there are several yet to be identified. In an excellent study by Dr. Josseline Kaplan and her associates, they estimate that gene mutations have been identified in only 47.5% of their patients.
Following is a listing of the known genes whose mutations can cause LCA. More information on these genes and genes whose mutations cause other types of retinal degeneration can be obtained on an excellent website, “RetNet” maintained by Dr. Steven Daiger.
1) CRX – Cone-Rod Homeobox
The protein product of the gene is known to control the synthesis of several functionally important genes in the retina such as opsin, the visual protein. It is thus very important in proper development of the retina. A specific CRX mutation will result in a dominantly inherited form of LCA while another mutation results in the more usual recessive form. LCA cases with CRX mutations are very rare. One study reports that CRX mutations are thought to cause 1-3% of LCA cases; another study on a different group of patients yields a figure of 0.6%. CRX gene mutations are associated with other retinal dystrophies as well as LCA.
2) AIPL1 – Aryl Hydrocarbon Receptor
Interacting Protein-Like 1 gene. The AIPL1 protein product is found in rod photoreceptor cells. Its function is yet unknown but may be involved in directing proper structure (folding) of important photoreceptor proteins. AIPL1 mutations account for 5-10% of recessive LCA cases as reported in one study and 3.4% in another.
3) CRB1 – Crumbs Homologue 1
This gene mutation was first seen to cause retinal degeneration in the eye of the fruitfly, Drosophila. The human gene is similar (homologous) to that in the fruitfly and a mutation also causes LCA-like vision loss. Other mutations in the CRB1 gene cause other retinal degeneration phenotypes such as a recessive form of RP. The function of the protein is unknown but is thought to be involved in development of retinal neurons. In the fruitfly, the protein probably functions in maintaining proper cell-cell interactions. In the human, one study estimates that CRB1 mutations account for 9-13% of LCA cases, another study reports a figure of 10%.
4) GUCY2D – Retinal Guanylate Cyclase
Guanylate Cyclase is a protein enzyme that makes a critical messenger in photoreceptors called cyclic GMP that is a major intermediate in the light-dark visual cycle. A Guanylate Cyclase mutation leads to an abnormal cyclic GMP concentration, inducing dysfunction and degeneration of the photoreceptor cell. In a strain of chickens, an analogous mutation in the guanylase cyclase protein also leads to severe, early (LCA-like) visual loss. In one study, GUCY2D mutations are reported to account for 10-20% of LCA cases; another study reports 21.2%.
5) LRAT – Lecithin Retinol Acyltransferase
The LRAT protein is an enzyme that is important in vitamin A metabolism in the visual process, catalyzing the first step in the visual cycle. The enzyme is specifically found in retinal pigment epithelial (RPE) cells. RPE cells adjoin retinal photoreceptor cells and partner with the photoreceptor cells in the visual process as discussed above. LRAT mutations profoundly disturb the normal chemical transformations of Vitamin A that are intrinsic in the visual cycle thus leading to photoreceptor cell dysfunction. Prevalence estimates of LRAT mutations are unavailable.
6) RPE65 – Retinal Pigment Epithelium 65
Like LRAT, the RPE65 protein is specifically expressed in retinal pigment epithelial (RPE) cells. It also is important in Vitamin A metabolism in the visual cycle. An excellent canine (Briard) model exhibiting a mutation in the RPE65 gene has been identified. Gene therapy studies on this model are in progress preliminary to human clinical trials that will test replacement of the RPE65 gene in the human eye. In one study, RPE65 mutations are reported to cause 6-16% of LCA cases; another study reports 6.1%.
7) RDH12 - Retinol Dehydrogenase 12
The RDH 12 protein, like the LRAT and RPE65 proteins, is involved in chemical transformations of vitamin A (retinol) in the visual cycle. Unlike LRAT and RPE65, however, it is selectively found in retinal photoreceptor cells, probably cone photoreceptor cells. Mutation of RDH12 leads to a severe, progressive form of LCA with extensive macular atrophy. In the human, RDH12 mutations are reported to account for about 4% of LCA cases.
8) RPGRIP1 – RPGR-Interacting Protein 1
THE RPGRIP1 protein is actually a member of a closely related family of proteins that, as the name implies, interacts with a protein named RPGR. RPGRIP1 and RPGR are localized in photoreceptor cell outer segments in the human. Here, the interacting proteins appear to be vital in transport processes into the outer segment. Disruption of this transport process would be expected to lead to retinal degeneration. In the human, one study reports that RPGRIP1 mutations account for 4-6% of LCA patients; another study gives a figure of 4.5%
9) TULP1 - Tubby-like Protein 1
The human TULP1 protein is very similar (homologous) to a protein previously identified in the mouse whose mutations lead to several problems including early progressive retinal degeneration. The protein is thought to function in facilitating the transport of important proteins like opsin to where they function in the photoreceptor outer segment. In a singl study, TULP1 mutations are reported to cause 1.7% of LCA cases.
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| 7. | Future Treatments and Cures
1) Clinical Considerations
Before any therapy for LCA is considered, the state of the patient’s retina must be determined. Although there is usually severe visual impairment from birth in LCA patients (i.e.low vision), there is little information on the morphological integrity of the photoreceptors or other layers of the retina. Fundus (back of eye) examination of LCA newborns often reveals the retina to be “fairly normal” in appearance although histopathological examination of a single prenatal, embryonic retinal sample demonstrated significant cell loss and other pathological changes.
Dr. J. Kaplan and her associates have examined numerous LCA patients and, in spite of the many genotypes, have phenotypically characterized the disease process into two subtypes, LCA1 and LCA2. The LCA1 group appears to have more severe manifestations of the disease while those falling into the second group retained more function and thus might be considered to be better candidates for treatment and ultimate sight restoration. The bottom line is that a thorough clinical examination of the patient must be performed to determine if they are indeed a candidate for a particular therapy.
For therapies such as Gene Therapy or Pharmamaceutial (neurotrophic) Therapy to be effective, enough photoreceptors need to remain alive and treatable. Luckily, there is a redundancy of photoreceptor cells in the human retina such that only a smaller percentage is needed for fairly good vision. In a similar vein, it is cone cells that are spared longer in most retinal degenerations and it is these cells that are most important for sharp and bright light vision in the human. Significant sight restoration therefore can theoretically occur even when most of the rod cells have degenerated with only a small number of cone cells present – hopefully in the macula.
Thus, there should be testing of the retina both morphologically and functionally to determine its state of degeneration. ERG and similar techniques can be used to determine any remaining functioning. A relatively new technique called Ocular Coherence Tomography (OCT) can be used to determine the thickness and integrity of the retina. Testing should not be done as a prelude to inclusion/exclusion to a clinical trial or treatment regimen. With regular testing of the structure and function of the retina, a better estimate can be made as to the progression of the disease and the possible condition of the retina when a therapy is available.
Thorough clinical testing should also be done of parents, other children and grandparents if possible. Subtle signs of degeneration may be detected in parents, possibly giving clinical clues as to the disease process.
2) Genotyping and DNA Banking
A small blood sample should be taken from the LCA patient as early as possible. From this sample, DNA can be prepared and tested for the known gene mutations described above. Along with efforts to find new LCA genes, the FRR is supporting the creation of a central repository, a “DNA Bank”, for such DNA samples. In this way, not only can immediate testing be performed but, if they are negative for the currently known LCA mutations, the samples can be retested at a later date for newly discovered gene mutations.
Genotyping is important since, if the mutation is actually identified, it lines up the patient for Gene Therapy when it becomes available. It also immediately gives the Ophthalmologist a much better view as to how that specific type of LCA usually progresses over time and the patient’s family can be better advised.
If possible, DNA samples should also be taken from family members. This makes the mutational analysis easier for the genetics investigator, especially in searching for a new gene mutation.
3) Gene Therapy
One of the best possibilities of a treatment and perhaps even a cure for LCA could come from Gene Therapy – more correctly, Gene Replacement Therapy. Simply, if there is a mutated gene that produces a malfunctioning protein or no protein at all, replacement with a normal gene in the proper cell type should result in synthesis of a normal protein, hopefully at a proper level with subsequent restoration of visual function. As outlined above though, Gene Therapy can only be successful if target cells (e.g., photoreceptor cells) are alive.
Before going to human clinical trial with any therapy, it is necessary to demonstrate proof of the efficacy (Proof of Principle) of a potential treatment as well as relative safety. For one form of LCA, the RPE65 mutation, we are lucky to have excellent rodent and canine models that also have RPE65 gene mutations and demonstrate early and severe vision loss. Extensive work has now been done on Gene Replacement Therapy in the canine model and the results are very promising as reported by Dr. Gustave Aguirre and his consortium of collaborators. After replacing the RPE65 gene in target RPE cells, significant vision is restored to all the animals. These results seem to be long term in that all of the dogs treated almost 5 years ago now yet have functional vision. Importantly, the therapy appears to be relatively safe with very few side effects noted and no long term negative effects. At least three other groups (USA, England and France) are preparing for clinical trials for RPE65 Gene Replacement. Similarly, Proof of Principle for Gene Therapy in a mouse model of LCA has been obtained by Dr. Tiensen Li and his coworkers. He has demonstrated the efficacy of replacing the RPGRIP gene in the retina of affected animals. This work will hopefully lead to successful gene therapy for human patients with this particular gene mutation. Thus, progress in effecting long term treatment of forms of LCA has been excellent. Human clinical trials are being planned that should be the models for all forms of LCA.
4) Pharmaceutical Therapy
What are the options while waiting for the gene mutation to be found prior to Gene Therapy or another treatment to be made available? In particular, is there a way to slow down the course of the disease, preserving photoreceptors until a permanent form of sight restoration is available? One option is Pharmaceutical Therapy.
Pharmaceutical Therapy can be defined as the use of any drug or natural agent to slow down the course of a retinal degenerative disease process. This method does not deliver a “cure” as theoretically Gene Therapy could but rather, a slowing down or even halting of the degenerative process. This affords the potential of many years more of functional vision to the patient.
Over the last few years, agents, drugs, natural growth factors, etc. have been identified that protect neuronal tissue against insult. Collectively, these are called neurotrophic agents or neuron-survival agents. The hallmark of their action is that they prolong the life of neuron cells such as photoreceptor cells. In many animal models of retinal degeneration, these different agents have been shown to substantially delay photoreceptor cell death, allowing for not only a longer period of vision but, in some cases, improved vision during this time.
Many agents have been shown to have neurotrophic activity in retinal degeneration. This field has been pioneered by Dr, Matthew LaVail who has compared activities of these agents in many animal models of retinal degeneration. One of the most successful is Ciliary Neurotrophic Factor (CNTF). Another example is a unique natural factor called Rod-Derived Cone Viability Factor. Dr. Jose Sahel and his collaborators have identified and characterized this protein which is particularly effective in slowing cone loss in retinal degeneration.
CNTF, is currently in clinical trial for forms of Retinitis Pigmentosa. The Phase 1 Study (safety) has been successfully completed and the Phase 2 Study (efficacy) is soon to commence. If successful, it should afford the first treatment for a rare human retinal degenerative disease and be available for general patient application in a few years. Since LCA is a special form of RP as described above, it is probable that many LCA patients could benefit from this type of treatment. Thus, while searching for the LCA gene in a particular patient, thought should be given to preserving the retinal photoreceptors as best as possible through Pharmaceutical Therapy.
5) Photoreceptor Cell Transplantation
A theoretically simple and appealing possibility for treatment of any photoreceptor degenerative disease is photoreceptor cell transplantation. In this technique, normal photoreceptor cells (sometimes with adjoining RPE cells) are surgically removed from donor eyes and transplanted into the photoreceptor space of the diseases retina. Most often, sheets of photoreceptor tissue are used, a process made easier because of the relatively flat, layered nature of the retina.
Retinal grafts have already been shown to survive and partially function in animal experiments. Drs. SriniVas, Magdalene Siler and Eugene de Juan have convincing experiments in rodent RP models that, after retinal transplantation, effective albeit limited connections are made with appropriate brain areas. Moreover, such transplantation actually promotes survival of remaining host retinal cells following transplantation probably because neurotrophic factors are elaborated in a tissue subjected to trauma such as the transplantation process. Thus, in addition to preserving vision through this neurotrophic effect, if methods can be developed to enhance the formation of functional connections between the graft and the host, retinal transplantation holds the potential for restoring vision to patients blind from advanced photoreceptor degenerations.
What is the main challenge? Studies from several laboratories have demonstrated that transplanted donor retinal tissue can survive in the subretinal, photoreceptor space but evidence that the transplanted tissue integrates with the host and forms functional synapses has been more limited. However, the group cited above has shown specific and enhanced retinal and brain electrical responses after photoreceptor cell transplantation. Importantly, an FDA-approved trial for photoreceptor transplantation is currently underway by Dr. Norman Radtke in Louisville, KY.
Future work in this area of research needs to concentrate on improving the integration of graft photoreceptor cells with secondary retinal neurons in the host tissue. However, it is now clear that the process of graft – host integration can, in fact, be modulated. Investigators in the field have been gaining in knowledge and expertise and it is hoped that these advances can be applied to the overall question of transplant functionality with a final, positive result in the human.
6) Stem Cell Therapy
Stem Cells are primitive, multipotential cells that have the intrinsic potential of developing into any cell type of the body, e.g., retinal photoreceptor cells. Stem cells are, of course, found in embryonic tissues. They also are present in many (if not all) adult tissues. In structures close to the adult human retina, true retinal progenitor cells (stem cells) have been identified and are currently being studied by several groups of researchers.
Stem cell therapy holds huge promise for replacing cells in the body, for example, those lost through a degenerative process such as inherited retinal degeneration. Specifically for LCA, stem cells could be transplanted into the photoreceptor space, differentiate and functionally take the place of the dead photoreceptors.
Significant problems of efficacy and safety remain to be overcome, however. For example, only partial differentiation towards a photoreceptor phenotype has been shown for stem cells by vision researchers. Although various biochemical markers unique to photoreceptors (e.g., the visual protein opsin) can be induced in the stem cells, a truly mature morphological and biochemical phenotype as well as light capture and synaptic functionality have yet to be demonstrated. Similarly, before human trials can start, significant safety issues need to be addressed. Stem cells, by definition, have virtually unlimited capacity for multiplication, a facet shared by cancer cells. It will be necessary in the future to demonstrate that stem cells can be managed once implanted in the eye such that they do not continue to grow in an uncontrolled manner.
In summary, stem cell therapy has great potential for treating retinal degeneration. This approach has the possibility of not only replacing dead photoreceptor cells but of allowing for reconstruction of the entire retina in the more severe retinal degenerations where secondary neurons degenerate as well as photoreceptor neurons. Much basic work needs to be done though before this promise is fulfilled.
7) Electronic Prosthetic Devices (the Chip)
Great progress is being made in work on electronic prosthetic devices - the “artificial retina” or “chip”. Animal and human testing is being done at many sites in the USA and in several countries such as Germany, Japan, Ireland, Belgium, Australia and Korea. In the USA, one company (Optobionics) is now 4 years into a Clinical Trial and another (Second Sight) is planning to begin a Trial in the relatively near future.
In a retinal degeneration, the prosthetic device would essentially take the place of the lost photoreceptor cells. Functionally, the photoreceptor cell captures the photic (light) energy and converts this energy to a chemical and then electrical signal and transmits this signal to secondary retinal neurons for processing and transmission to the brain. The retinal prosthetic device has been designed to fulfill all these functions. First, a small camera most probably attached to patient’s eyeglasses would capture the visual images. The camera would send these images to the prosthetic device that had previously been implanted in the eye - attached to the remaining, secondary neuronal cells of the retina. In several subsequent steps, the initial light signal is converted into an electrical signal that is transferred from the chip to the secondary neurons and ultimately to the brain. This internal device consists of an array of electrodes that directly signals and electrically excites secondary retinal neurons.
There has been great progress in chip development over the last few years. Yet, the challenges in producing a functional sight-restoring prosthetic device are significant. It appears, for example, that data from the Optobiobics Company and their academic collaborators demonstrate that their subretinal chip is itself ineffective in improving vision. Rather, it appears that the device acts to induce an “injury response” – eliciting the elaboration of endogenous neurotrophic factors. These neurotrophic factors stimulate remaining neurons to perform better, i.e., “sight restoration”. As of a few months ago, the “improvement” in the patients originally seen after implantation of the Optobiobics chip seemed to be fading with time. The bright side of these essentially negative data is that it now may be that any chip implantation (possibly acting as an “insult” to the retina) could lead to the production of neurotrophc factors. This serendipitous finding could form the basis of enhanced photoreceptor activity after chip implantation.
Another very important finding from the Optobionics clinical trial is that chip implantation appears to be a safe procedure. Few negative effects of implantation were detected allowing for human testing to proceed in a confidant manner.
As mentioned above, several prosthetic device projects are underway across the world. Other than the Optobionics work, one of the most advanced is that mounted by Dr. Mark Humayun (USC Medical School, Los Angeles, CA) and his collaborators in conjunction with a company called Second Sight. Preliminary animal and human testing has been successfully completed and a clinical trial is planned for the near future. The device used by the Humayun/Second Sight consortium has 16 electrodes in contact with the retina. It is a robust electrical device of a different design from the Optobionics device. Indications from a limited number of human implants indicate a high degree of safety and even some improvement in vision using this device. Devices with many more (64, 128, 1000, etc) electrodes are being tested in the laboratory, devices that could lead to a high degree of visual restoration in LCA patients.
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| 8. | Summary and Conclusion
In the last few years, much progress has been made in understanding the physical characteristics and progression (phenotypes) of the different types of LCA as well as the gene mutations (genotypes) causing the disease process. Mutations in 9 different genes are now known to cause different forms of LCA, probably accounting for roughly half of the patient population.
A number of modes of therapy are in different stages of development. In particular, a clinical trial on the neurotrophic agent CNTF is already in progress (Pharmaceutical Therapy) while a trial using Gene Replacement Therapy for the RPE65 LCA mutation should begin soon. Transplantation and stem cell therapy hopefully will afford treatments in the future. Similarly, electronic prosthetic devices show great promise – one type already in clinical trial and another to soon to begin FDA-approved testing in RP patients.
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©2010 The Foundation for Retinal Research and its licensors.
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