12
返回列表 回复 发帖

版主

Rank: 7Rank: 7Rank: 7
11#
凤凰涅盘发表于 2012-2-11 11:08 | 只看该作者
10# 凤凰涅盘
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.


9. 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 17 different genes are now known to cause different forms of LCA.
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 human trial using Gene Replacement Therapy for the RPE65 LCA mutation began in 2008. 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.
生命不息，战斗不止。
回复 引用

TOP

版主

Rank: 7Rank: 7Rank: 7
12#
凤凰涅盘发表于 2012-2-11 11:09 | 只看该作者
11# 凤凰涅盘
10. Is Anyone Working On the Specific Gene Mutation in Our Family
By Dr. Gerald Chader
Even though it is a very rare disease, committed researchers and clinicians are making a strong effort to find the causes and the cures for LCA. As of today, 17 different genes have been identified whose mutations cause LCA. Proportionally, this is probably higher than for any other comparable family of diseases. It is estimated that these 17 gene mutations account for about 70% of all LCA cases. Several animal models have been identified or genetically constructed that have the same gene mutations found in humans with LCA. Researchers are using these to test for efficacy and safety for treatments that could be used in human clinical trials. Following are a number of LCA gene mutations on which progress is being made in preclinical testing and two mutations on which clinical trials have already started.
Clinical Trials in Progress:
1) RPE65 mutations (LCA2) – Three laboratories (Drs. Ali, Jacobson, Bennett and their coworkers) have been working on gene replacement therapy for over 3 years now. Previously, preclinical studies in animal models exhibiting mutation in the RPE65 gene were very successful. In the current clinical trials, results for safety and efficacy for all the groups is good. These trials continue on more patients and, importantly, on younger patients in hopes of gaining even a better visual improvement with treatment. Recent evidence from Bennett et al (2011) demonstrates brain (visual cortex) responses after gene therapy suggesting that gene therapy “resulted in … sustained and improved visual ability” … “despite severe and long-term visual impairment”.
2) LRAT and RPE65 mutations – Mutations in these genes lead to the synthesis of defective proteins (either the LRAT or the RPE65 protein) that are very important in the photoreceptor visual cycle in maintaining proper vitamin A metabolism. Without proper functioning of these proteins the visual cycle stops, vision is dramatically degraded and photoreceptor cell degeneration results. A clinical trial is in progress by Dr. Rob Koenekoop in conjunction with the QLT Company that is testing a synthetic retinoid (i.e., type of vitamin A compound) in a small number of patients that will circumvent the genetic mutation. To date, there has been significant improvement in a number of visual parameters including visual field and visual acuity in the treated subjects.
Preclinical Testing that Precedes a Clinical Trial:
3) CRB1 mutations – CRB1 mutations are found in 10-15% of LCA cases. Preclinical work by Dr. Jan Windhols of the Institute for Neuroscience in the Netherlands and Dr. John Flannery at UC Berkeley in the USA could lead to new treatment regimes for this form of LCA. These investigators are developing new forms of AAV vectors that can be used in gene therapy techniques. Vectors are modified viruses that carry therapeutic genes into target cells. They are made safe for use by removing intrinsic viral genes which allow for replication of the virus before the therapeutic gene is inserted. One particularly good candidate for gene therapy use is the AAV virus vector system and it is variation in its structure and function on which there is a current research focus.
4) Crx mutations – An animal model has been produced in which cell replacement therapy is being tested. Dr. Tom Reh and coworkers at the Univ. of Washington are doing experiments to see if human embryonic stem cells (hESCs) can be used to replace retinal neurons after damage and degeneration in a Crx-deficient mouse. Early results are very promising in that the stem cell therapy has been able to restore some function in the test retinas. Importantly, a company specializing in stem cell therapy is interested in taking this work to human clinical trial if the animal experiments show safety and efficacy.
5) Lebercillin (LCA5) mutations – A consortium of investigators is working to see if gene therapy could be used to restore function in patients with the very rare lebercillin mutation. These investigators include Drs Frans Cremers, Anneke den Hollander and Ronald Roepman in the Netherlands, Dr. Patsy Nishina and Dr. Jean Bennett in the USA and Dr. Rob Koenekoop in Canada. In preclinical work, the group has successfully produced an excellent animal model of LCA5 using sophisticated techniques of molecular biology and is currently testing to see if gene therapy can replace the mutated gene with a normal copy and restore function in affected young mice. If successful, human trials are planned.
6) GUCY2D mutations, LCA1 – GUCY2D mutations account for about 20% of the LCA population. Based on excellent work on a chicken model of the GUCY2D mutation by Dr. Semple-Rowland at the Univ. of Florida, she has demonstrated restoration of functional vision in these animals using a novel form of gene therapy (2011). Two other studies (Ali et al. 2011 and Hauswirth and coworkers, 2010) have used mouse models to demonstrate functional and behavioral restoration of vision using gene replacement of the guanylate cyalase-1 (Gucy2d) gene. For humans, cone photoreceptors are the most important type of photoreceptor cell since they, not rods, mediate sharp-, bright-light and color vision. Cone cell preservation was observed in these studies, indicating probably success in vision preservation in human testing in the future. A very recent study extends the time of examination in treated mice to over 1 year. Cone cell function was observed throughout this time, again giving good evidence that there should be not only efficacy in the human but a long-term effect.
7) CEP290 and IQCB1mutations – Patients with the CEP290 mutation (NPHP6) constitute the largest percentage of LCA patients and have a problem in function of the cilium area of the photoreceptor cell. A closely related “ciliopathy” is NPHP5 (IQCB1) LCA. Luckily, patients with these mutations retain a significant amount of intact photoreceptor architecture in the cone-rich central portion of the retina even though they exhibit very poor visual function. A mouse model of the CEP290/NPHP6 disease exhibits the same anatomical integrity as well as preserved visual brain pathway. In a fish model of the disease generated by investigators at the University of Iowa (including Dr. Ed Stone), vision has recently been restored in a fish CEP290-mutant model using gene therapy. This work and that by other investigators suggests that cone photoreceptors should be the main gene therapy target in the NPHP5 mutations as well as the CEP290/NPHP6 mutations when clinical trials begin.
8) RPGRIP-1 mutations – RPGR-interacting protein-1 is another important protein in the specialized area called the “cilium” of the photoreceptor cell whose lack or dysfunction leads to a form of LCA. Dr. Tiansen Li and coworkers at the Harvard Medical School, Boston, MA have produced a good mouse model of this form of LCA and used gene therapy for replacement of the RPFRIP-1 gene. After therapy, production of the RPGRIP-1 protein was restored in the photoreceptor and the protein was transported to its normal position in the cilium. Moreover, there was better photoreceptor cell survival and preservation of morphology and electrical function in the treated animals. Drs. Jacobson, Stone and their coworkers have closely examined human subjects with RPGRIP1 mutations and found that such patients have “treatment potential” in that these patients maintained relatively good preservation in the central portion of their retinas, the area most important in humans for good visual acuity.
9) AIPL1 mutations – Drs. Li, Ali and coworkers have intensively studied mouse models with APL1 mutations that reflect the clinical spectrum of human APL1 phenotypes, for example, AIPL1 patients who have different rates of degeneration. They have established that different viral vector systems are effective in APL1 gene replacement. Specifically, there was photoreceptor cell preservation and restoration of cellular function in treated animals. As with the RPGRIP-1 patients cited above, clinical investigators have evaluated patients known to have APL-1 mutations for their potential for successful gene therapy. In contrast to the RPGRIP-1 patients though, significant macular degeneration was observed although some sparing was found in the peripheral retina. Drs. Simonelli and coworkers in Italy have also evaluated Italian patients with APL1 mutations and feel that future human gene therapy of such patients should be productive based on their finding and on the success of such therapy in the mouse model.
10) MERTK mutations – For many years, the RCS rat has been used as a model in RP studies. The MERTK mutation in RPE cells makes them incapable of phagocytizing shed tips of photoreceptor outer segments that normally occurs on a daily basis. There is a resultant buildup of a debris layer between the photoreceptor and RPE cells and rapid photoreceptor degeneration. Besides RP, MERTK mutations can also cause a rare form of LCA. Investigators such as Dr. Ali and coworkers in London have demonstrated that AAV-mediated gene transfer can slow photoreceptor loss in the RCS rat model of retinal degeneration. Morphologically, there is a decrease in debris buildup demonstrating at least partial restoration of function in the RPE cells. The number of remaining photoreceptor cells was also higher in the treated vs. control retinas. This success could pave the way for human trials in the future.
生命不息，战斗不止。
回复 引用

TOP

版主

Rank: 7Rank: 7Rank: 7
13#
凤凰涅盘发表于 2012-2-11 11:10 | 只看该作者
12# 凤凰涅盘
11) IMPDH1 mutations - Depending on the area of the gene affected, IMPDH1 mutations can cause either LCA or a form of autosomal dominant RP classified as RP10. This spectrum of mutations and disease phenotypes has been well characterized by investigators such as Dr. Steve Daiger at the University of Texas in Houston. TX. Dr. Peter Humphries and his coworkers in Dublin, Ireland have applied gene therapy to a mouse model of RP10 and found it to prevent photoreceptor degeneration and to preserve synapse conductivity. It has yet to be demonstrated though that this work is applicable to the LCA disease phenotype.
12) RDH12 mutations – There are many members of the retinol dehydrogenase (RDH) family of protein enzymes, classically thought to participate in vitamin A molecular conversion in the retina. Recent work though indicates that the specific RDH12 member of this family protects the retina from oxidative damage with disruption of the gene and protein leading to retinal degeneration. A “knockout” mouse has been engineered in which the RDH12 gene is disrupted so the biological effects of deleting the gene and protein can be studied. With this model available, gene replacement therapy can also be performed to test for safety and efficacy of the procedure before attempting human clinical trials.

Laboratory Experimentation:
13) RD3 mutations LCA12 - Although the RD3 mouse model of retinal degeneration has been known for many years (1993), it was only in 2007 when the gene mutation causing the disease process was identified by a large consortium of investigators. The RD3 protein seems to perform many important functions in the retina Molday and coworkers have recently shown that it is critical for synthesis of a signaling molecule in the photoreceptor cells called cyclic GMP, lack of which could lead to photoreceptor cell death. In the mouse, a variable phenotype is observed with siblings with the exact same mutation exhibiting different levels of degenerative severity. Danciger and colleagues have begun to catalog genetic modifiers for this effect, i.e., genes/alleles that influence the inherited degenerative process. Although preclinical therapeutic experiments are yet to start on the RD3 mutation, excellent rodent and canine models are available that are similar to humans with the RD3 mutation.
14) SPATA7 – Mutations in the human SPATA7 gene causing LCA were only reported in the scientific literature in 2009. Since then, a few publications have described the screening of SPATA7-specific patients within the LCA population ( 1.7% of cases of childhood retinal dystrophy), the genetic spectrum of SPATA7 mutations and the delineation of the associated disease phenotype. Even though there is severe visual loss in infancy, some preservation of photoreceptor structure has been described in the central retina. This gives hope for successful therapy in restoring at least some visual function in an appropriate animal model and ultimately in the human.
15) TULP1 mutations – Some mutations in the TULP1 gene can lead to LCA while others lead to retinal degeneration that is of an RP phenotype. A number of clinical reports are in the scientific literature describing the characteristics of the degeneration in specific families (Suranamese, Algerian and Dominican). A good mouse mode has been developed and characterized. It demonstrated an early-onset retinal degeneration but seems to be normal in other regards. The availability of the model would allow for testing of different types of therapy in the future.





©2012 The Foundation for Retinal Research and its licensors.




Site Powered by Web Construction Set
生命不息，战斗不止。
回复 引用

TOP

版主

Rank: 7Rank: 7Rank: 7
14#
凤凰涅盘发表于 2012-2-11 11:23 | 只看该作者
12）RDH12突变 - 有许多的视黄醇脱氢酶（木RDH）的蛋白水解酶家族成员，参与维生素在视网膜的分子转换。虽然最近的工作表明具体RDH12这个家庭的成员免受破坏，导致视网膜变性的基因和蛋白的氧化损伤视网膜。一个“拳头”老鼠已经设计，其中RDH12基因被破坏，因此可以删去的基因和蛋白质的生物效应研究。可用这个模型，也可以进行基因替代疗法，试图人体临床试验之前，测试程序的安全性和疗效。
生命不息，战斗不止。
回复 引用

TOP

金牌会员

Rank: 6Rank: 6
15#
坚决抵制日货发表于 2012-2-11 22:43 | 只看该作者
这多英语,看不懂
不到最后，我不认输
回复 引用

TOP

12
返回列表