Aging&Vision A publication for Practitioners, Researchers and Educators Volume 17 Number 2 Fall 2005 A Message from the President and CEO of Lighthouse International by Tara A. Cortes, RN, PhD As the new President of Lighthouse International, I am keenly aware that vision impairment touches nearly everyone -- either personally or through friends and family. As baby boomers approach their later years, we expect that the number of people older than 65 will multiply three-fold over the next 20 years. The incidence of age-related vision loss will rise rapidly in tandem with our aging population, making vision impairment an increasingly pressing public health issue. Fortunately, advances in vision research, medical treatments for age-related eye conditions and adaptive technology hold great promise for a positive impact on the field of vision rehabilitation and the lives of millions of people facing vision loss. These advances are changing the landscape of treatment and will present us with both challenges and opportunities. The following are some of the advances for patients with the four leading causes of vision impairment. Several are reported in this issue: - Glaucoma -- new research is ongoing in the regeneration of damaged optic nerves. - AMD -- recently, two genes related to AMD have been isolated; new treatments are on the horizon to stop the destruction of the retina by wet AMD and help patients retain, and even recover, visual acuity; and the drugs currently on the market are only the beginning for the pharmaceutical industry. - Diabetic-related eye disease -- better diabetes management techniques will continue to be a top priority and will result in earlier detection of the disease as well as prevention; improved treatments for retinal damage are already available and will play a significant role in affording more vision over a longer period of time. - Cataract -- new intraocular lenses, which provide vision at all distances, are already on the market. One of the challenges for vision rehabilitation care will be appropriate reimbursement. Vision impairment must be recognized as a public health issue and vision rehabilitation must be acknowledged as a necessity. Without vision rehabilitation interventions, persons with low vision are at risk for falls, injuries, depression and the inability to continue activities of daily living. Skilled professionals can assist people with low vision to live as independently as possible. Adequate Medicare and other private insurance reimbursement must be available to assure older adults have access to appropriate services and adaptive devices. With this reimbursement, the more costly and complicated care can be avoided or delayed. The Lighthouse is dedicated to maximizing the positive impact of scientific, medical and technological advances through increased public awareness campaigns, continued outreach to eye care providers, ongoing training of vision rehabilitation professionals and enhanced advocacy efforts. We look forward to working with you on these fronts to help people of all ages overcome the challenges of vision loss. In This Issue - Artificial Sight: The Retinal Prosthetic Chip - The Lighthouse Role in the History of Vision Rehabilitation - Share the Wealth of Knowledge: Continuing Education and Training for Professionals - - Optic Nerve Protection and Regeneration After Disease and Injury (sidebar) Lighthouse International is able to provide Aging & Vision thanks to the support of caring people like you. You can help support this and other Lighthouse programs and services by making a donation today at www.lighthouse.org/donate or by calling (212) 821-9437. Thank you! Artificial Sight: The Retinal Prosthetic Chip by Gerald J. Chader, PhD Retinal degenerative diseases affect millions of Americans and similar numbers of people in Europe. It is estimated that 30 million people are affected worldwide. Although some treatments for these conditions are available, or are being planned, they are dependent on the integrity of the retinal photoreceptor layer, the cell type most vulnerable in retinal degenerative diseases. What is available to patients whose photoreceptor cells die, as in the later stages of these diseases or in aggressive, early onset retinal degenerations? The answer may lie in tiny electronic devices implanted on the neural retina. The Need To date, there is no effective treatment for the millions of patients with dry AMD, or for those with retinitis pigmentosa and allied diseases. Although the number of patients with RP is lower than those with AMD, RP can cause marked vision loss or blindness even from birth. This can create a severe socioeconomic burden for individuals as well as society for the lifetime of otherwise healthy people. A retinal prosthetic device ("chip") affords the best possible opportunity to at least partially restore functional vision for the widest number of patients with moderate to severe vision impairment caused by retinal degeneration. Multiple Approaches to Chip Development and Placement In simple terms, the chip can functionally take the place of dying or dead photoreceptor cells. To achieve this, groups around the world are taking different approaches with regard to the type of device used and its placement. Devices that abut the optic nerve and ones that provide suprachoroidal-transretinal stimulation are being studied. Another novel approach involves the directed migration of secondary retinal neurons into spaces or pores of the implanted chip, potentially allowing for closer and more specific interaction. Bypassing the eye completely is the aim of those developing cortical devices. However, the two approaches that are farthest along in development are subretinal and epiretinal implants. The subretinal approach, in which the device is placed between the RPE cells and the remaining retinal layers, has the advantage of the chip being placed in a "photoreceptor" position such that it has the potential to interact with natural target neurons of photoreceptors like bipolar cells, etc. However, surgery is fairly disruptive. In the epiretinal approach, the device is placed on the vitreal surface of the retina. This is less disruptive and provides more flexibility in component placement. However, the target neurons are less well defined, and it appears that more complex stimulus algorithms are needed. Subretinal Implants The basic chip designed by Drs. Alan and Vincent Chow of the Optobionics Company is perhaps the archetype of the subretinal devices and is farthest along the clinical pathway. This passive device, the Artificial Silicone Retina (ASR), is composed of tiny solar cells that, when activated by light, will theoretically send an electrical signal through the secondary neurons of the retina (e.g., bipolar cells, etc.) and down the optic nerve to the brain. A potential problem with such passive devices is that they may generate too little power to be effective. Most other chip designs have devices that increase the output power at the retina level. In spite of this potentially serious problem, the Optobionics device has been in FDA- approved clinical testing for about five years. Importantly, safety issues seem to be well in hand since the retina tolerates the implant well. Vice versa, the chip seems to tolerate the hostile environment of the subretinal space, although more work on this issue needs to be done. To the surprise of many, several of the patients chosen for the initial Safety Phase 1 part of the trial reported improved vision. This was mainly "subjective" improvement in areas such as brightness, contrast, visual field and color discrimination. Subsequently, Optobionics has made great strides in developing more objective methods of testing and has confirmed the early improvement. In the last two years though, a decline in vision has been found in many of the patients. Also, an odd phenomenon was noted. Essentially, the visual improvement encompassed a considerably larger area than that subserved by the tiny chip itself -- i.e., there was visual improvement in retinal areas relatively far from the device. A series of collaborative research efforts in test animals using active and inactive devices has led to the conclusion that chip implantation probably induces the secretion of natural neurotrophic factors by retinal cells that could lead to both prolonged life of retinal neurons and improved function. Dr. Chow postulates, "Persistent improvements in visual function in the retina both adjacent to and distant from the ASR implant continue to suggest a neurotrophic benefit of the chip. …" This "injury-response" mechanism is reminiscent of retinal transplantation experiments in the 1980s, when sham-operated retinas in test animals had "improved" visual responses comparable to those receiving actual photoreceptor transplants. Currently, Optobionics is continuing its clinical investigations as well as further examining the possible neurotrophic effect of the chip. Epiretinal Implants Among the several epiretinal efforts, that of the consortium of investigators led by Drs. Mark Humayun and James Weiland at the University of Southern California and the Second Sight Company is farthest along in clinical testing. These investigators have impressive collaboration and support from the NSF, along with the US Department of Energy and five of its National Research Laboratories. As conceived by this group of investigators, the epiretinal chip is much more complex than the Optobionics chip. A small video camera will be hidden behind a pair of glasses worn by the patient to initially capture the visual image. These images will be relayed to a small computer worn on a belt, then to an antenna behind the ear, which will finally send the signal to the epiretinal implant within the eye. Currently, this implant has 16 individual electrodes that can interact with retinal neurons, but 32 arrays and higher are being tested for future implantation. In this design, the electrical signal is greatly amplified to within the range thought to be recognized by the retina. So far, the epiretinal team has implanted six devices in patients and, as with Optobionics, has found the devices to be relatively safe. Also as with the subretinal implants, some efficacy has been reported -- again, surprisingly, since the initial patients chosen had very poor vision, befitting the Phase 1 Safety part of a Clinical Trial. Shape, spatial and motion discrimination were improved in several patients, some of whom had no functional vision prior to the beginning of the trial. This epiretinal effort is currently continuing with high expectations for success. Implantation of devices with large numbers of electrodes is certainly possible, theoretically allowing for a better visual image. Chip Challenges So what still remains to be done? In the current and proposed clinical trials, there is a need to prove long-term safety for both the human subject and the electronic implant. Also, efficacy has to be demonstrated conclusively -- efficacy that hopefully lasts for years, if not for the lifetime of the patient. Testing procedures need to be improved. Psychophysical tests need refining, as well as the application of tests such as OCT and electrophysiological recordings from the retina and brain that demonstrate not only "vision" at the retinal level but also in cognitive centers that yield functional results. An important problem that ultimately might limit the usefulness of the chip (even if it does prove to work in future) is the phenomenon of "retinal reorganization." It is well known that retinas affected with an inherited degeneration sustain damage in the inner retinal layers (bipolar, ganglion, etc., cells) as well as lose photoreceptor cells. Some inner retinal neurons die (up to 70% of ganglion cells in some eyes with RP) and others "remodel," sending out axonal-like processes (neurites) in areas of heavy photoreceptor loss. These and other abnormalities have been cataloged by the work of Drs. Ann Milam, Mark Humayun and, more recently, the elegant work of Dr. Robert Mark. The neuritic sprouts become associated with surfaces of inappropriate secondary neurons and glia, and may simply be searching for stimulatory input and contact. This could then contribute to the ERG abnormalities seen in RP patients and speed their progressive decline in vision. Due to CNS neuronal plasticity, however, it very well may be that some of these abnormal effects could be reversed after the imposition of a more normal electrical input from the chip. Whether the chip (subretinal or epiretinal) works is the critical question, but an intriguing corollary is whether neurotrophic factors induced by chip implantation (surgery and/or electrical stimulation) play a role in visual "improvement" in implanted patients. In the case of the Optobionics device, this does seem to be the case. Thus, supplying exogenous neurotrophic agents at the time of implantation may enhance both the acute and chronic results. Conclusions Chip implantation may be the final hope for patients with retinal degenerations in which the disease has progressed to a point where most or all of the photoreceptors are gone and the more conventional therapies (gene therapy, pharmaceutical therapy) are not applicable. Although there are areas of chip development that still need more work -- the electronics, the biological interface, brain recognition, etc. -- significant progress has been made, as attested to by the two current clinical trials in progress and the many groups around the world working on different chip model systems. Thus, the future of the chip looks bright not only for low-grade mobility for patients but also in enhancing face recognition and reading ability. In the final analysis, the cost for development of the chip is substantial, but who can put a price tag on restoring a person's sight? Gerald J. Chader, PhD, is the Chief Scientific Officer, Doheny Retinal Institute at USC Medical School. (Callout) Chip implantation probably induces the secretion of natural neurotrophic factors by retinal cells that could lead to both prolonged life of retinal neurons and improved function. (sidebar) Help Us Spread the Word! As the Lighthouse celebrates its Centennial, championing the benefits of vision rehabilitation for people with vision loss continues to be a top priority. Join us to help ensure that people with impaired vision seek vision rehabilitation services in their home communities by ordering our free publication, "Vision Loss Is Not a Normal Part of Aging," which has been reprinted thanks to a special grant from Novartis Ophthalmics. This booklet explains the difference between normal changes in vision, which we all experience as we get older, and changes that are caused by disease. You can help us raise awareness by sharing this booklet with your community. "Vision Loss Is Not a Normal Part of Aging" is available in both English and Spanish. Order your free copies (with a maximum of 50 copies per person) by e-mailing gobando@lighthouse.org or faxing us at (212) 821-9705. The Lighthouse Role in the History of Vision Rehabilitation by Gregory Goodrich, PhD In today's society, most people know someone who has low vision, but such familiarity is a very recent development. Just 50 years ago, the major area of interest and concern for professionals working with people who were visually impaired was blindness -- people who had little, if any, useable vision. But during the last half-century, an interesting thing happened: people started living longer. Life expectancy increased from less than 50 years (in 1900) to well over 75 years (in 2000). And while few would argue that this increased longevity is a bad thing, longevity often brings with it age-related macular degeneration, adult-onset diabetes or other eye diseases related to aging. The diseases that affect the visual system most commonly cause low vision and not blindness; consequently, low vision has developed as a relatively new area of interest, but one that affects millions of people. Important Shift in Terminology Fifty years ago, people with low vision were labeled "visual defectives" or "partially blind." The emphasis implied by these labels was not on what the person could see, but on what they could no longer see. As a consequence, individuals with low vision were often taught to act as though they were blind. Many people who were labeled "visual defectives," or some other pejorative term, often rejected the negative label and expressed their frustration -- they knew they could see, but could not find help to see better. By the early 1950s, the needed help was being developed. The Lighthouse didn't invent the field of low vision, but it did name it. At that time, Drs. Eleanor E. Faye and Gerald Fonda noted the negative impact of terms such as "visual defective." Dr. Faye suggested the term, "low vision," as a more accurate and less pejorative description, and one that emphasized the important role of vision in a person's life. Drs. Faye and Fonda started using the term and their colleagues adopted it. Today, low vision is an almost commonplace term that is widely used not just in the United States but also throughout the world to describe those who have reduced visual capacity. It is also used to describe the specialized services that people with low vision receive -- the devices and training that allows them to use their vision as a normal part of their lives. Low Vision Devices When the field was first named in the 1950s, low vision services provided limited options. Few tests were available to assess visual acuity or visual fields. And for those few clinicians who, like Drs. Faye and Fonda, were skilled in treating low vision, the devices they could prescribe were limited to a small number of magnifiers. More sophisticated devices such as closed circuit televisions would not become readily available until the 1970s, and accessible computers would not become a standard fixture in low vision clinics until the late 1980s. Yet the seeds of these marvelous developments in low vision were already sown in the 1950s, and from New York to California, the field's pioneers were improving their own skills, inventing new and useful devices, and training the next generation of low vision specialists. It is often not recognized, but one critical area in the development of low vision is the emergence of a specialized industry to design and manufacture low vision devices. Almost from the earliest days, the Lighthouse has played an important role in fostering the emergence of the manufacturers by defining the needs for new devices and often suggesting important design elements. Whether it is today's illuminated magnifier or a complex electronic device, the Lighthouse has probably played a role in the innovative ideas that spawned the device, in the evaluations that perfected it or by facilitating the device's distribution to low vision practitioners. Lighthouse researchers and clinicians are, and have historically been, very active in the development of the devices we now take for granted in our low vision clinics. Low vision devices have an important place in low vision services, but before the right device(s) can be prescribed for the person with low vision, the clinician needs to assess his or her needs and visual capabilities. Starting with a few simple tests available to the clinician of 50 years ago, today's doctor can take advantage of a wide array of vision test equipment to assess visual status and improve functional vision. Many people have contributed to the development of low vision testing and assessment tools, but clinicians and researchers at the Lighthouse have historically played important roles in the design and evaluation of these tools -- whether it be in developing tests of visual acuity or contrast sensitivity, or tests of driving ability. A Broader Array of Professionals Fifty years ago, low vision services were largely the province of low vision optometrists, ophthalmologists, orientation and mobility instructors, rehabilitation teachers and special educators. We now recognize that low vision doesn't just reduce one's ability to read or to walk around safely and efficiently; low vision affects virtually every aspect of one's life, and today's field of low vision encompasses a wide array of professionals who offer psychological and social services for both the individual, as well as family members. Psychologist Helen Mehr, who was married to Edwin Mehr, OD, one of the field's pioneers, helped us recognize the importance of social and psychological factors. Today, researchers around the world study a wide range of issues, from aging and families to spirituality, as they relate to low vision. Researchers at Lighthouse International's Arlene R. Gordon Research Institute are on the cutting edge and, as a result, psychological services available today are better than ever before. Low vision remains a historically young field -- 80% of all publications in the field have been written within the past 20 years -- but it's a field of rapid advancement and enormous potential to improve the lives of people once thought of as "visually defective." Thanks to researchers and talented clinicians at Lighthouse and around the world, the lives of people with low vision can be vibrant, independent and productive. And today's society can benefit from the active participation of its citizens with low vision every bit as much as it benefits from those who are sighted. Dr. Goodrich is a research psychologist at the Veterans Affairs Palo Alto Health Care System in California. He is also President of the Association for Education and Rehabilitation of the Blind and Visually Impaired, and Treasurer of the International Society for Low Vision Rehabilitation. (callout) "low vision" ... a more accurate and less pejorative description, and one that emphasized the important role of vision in a person's life (Callout) Today's field of low vision encompasses a wide array of professionals who offer psychological and social services for both the individual, as well as family members. Share the Wealth of Knowledge: Continuing Education and Training for Professionals by Karen R. Seidman, MPA Fledgling. Nascent. Emerging. If asked, many would use these words to describe professional training activities in low vision care. Why? Some might say it's because low vision care itself is still a young field. Although optical devices were under development in the first half of the 1900s, it wasn't until much more recently that the techniques for examining and prescribing for patients with low vision were being developed in a way that could be replicated. Consider that: - The widely used modified ETDRS chart was introduced as part of the low vision exam only in the late 1980s. - While the American Academy of Ophthalmology established its first low vision committee in 1976, its nationwide SmartSight low vision initiative did not emerge until 2005. - A standardized curriculum for Rehabilitative Optometry (care of the patient with low vision) was first added to OD training in 1982. - The World Health Organization recognized low vision as a part of Vision 2020: The Right to Sight (the worldwide effort to eliminate avoidable blindness by the year 2020) in 1996. - Certified Low Vision Therapists first became a part of the low vision team in 1997. - The first textbook on low vision specifically for ophthalmology residents was published by Lighthouse International in 2000 in English, and in 2003 in Spanish. But this young field has had its share of early pioneers (Feinbloom, Sloan, Faye, Mehr & Fried, Fonda, Hellinger, Colenbrander, to name just a few) who contributed significantly to developing clinical approaches and tools. And, in addition to their vast clinical contributions, other prominent founders (including Faye, Rosenthal, Hood, Hyvarinen, Veitzman and Medina) also have dedicated themselves to training new professionals worldwide, giving ophthalmologists, optometrists, nurses, technicians, and vision and rehabilitation professionals the skills they need to expand available services. The need for what was then called "manpower" training in low vision care was recognized as early as 1975. Two philanthropic foundations in New York City helped Lighthouse Continuing Education get its start at providing formal, accredited training grounded in clinical practice, from which over 16,000 professionals have benefited to date. Others who joined the training arena have included the Academy of Optometry and the American Optometric Association, the Pennsylvania College of Optometry, Johns Hopkins University, the American Academy of Ophthalmology, optical device manufacturers, state optometric associations and ophthalmological societies, regional conferences and independent providers. Online education in this field has just begun to emerge. In recent years, training in low vision and vision rehabilitation has become a focus of global attention. This is evident in the Vision 2020 regional/national plans that have been adopted in areas such as Latin America, Asia and Africa. It is noteworthy that each plan, in its own way, highlights the imperative to provide existing and future professionals with the necessary skills to assess vision loss and offer appropriate remediation as one strategy toward achieving the project's ultimate goal. Yet today, the number of providers of low vision care and vision rehabilitation is still inadequate to meet the burgeoning demand. The "training of trainers" is one important way to approach this problem. When professionals engage in training that enhances their clinical skills and also provides them with teaching techniques, curriculum and strategies for sharing the information with others, there is an exponential benefit to training initiatives. Such has been the case with Lighthouse International's programs in Mexico, the Dominican Republic, India and the Middle East. Collaborative agreements with selected vision and vision rehabilitation centers in each of these areas along with specialized training have made it possible for local professionals (ophthalmologists, optometrists and rehabilitation specialists) to become adjunct faculty members able to present courses in their regions on their own or with Lighthouse experts. The regional knowledge, cultural awareness and language skills that these adjunct faculty members bring to the delivery of course material is unparalleled, as are the opportunities for many more courses to be offered in more places around the world. The founders of Lighthouse International 100 years ago, Winifred and Edith Holt, surely would have been avid supporters of this type of initiative. As early as 1915, Winifred traveled to France, Italy, Poland, China and Japan where she helped to establish vision rehabilitation services and provide new skills for those who were seeking to help blinded World War I veterans and others. The Lighthouse's current work with the Ebsar Foundation, a not-for-profit organization based in Saudi Arabia, offers an excellent example of this training model. The Foundation wanted to establish low vision/vision rehabilitation services at its center in Jeddah, and also to introduce these services throughout the Maghrabi Eye Hospitals, a network of hospitals in the Middle East, Africa and Asia. In a consultative arrangement with the Lighthouse, training in clinical care was provided for selected professionals. They also received extensive training to be prepared to share this information with other professionals. As a result, two on-site courses in the region have already been conducted using joint faculty and a third will take place in December 2005. More than 40 additional professionals from the region have taken the Lighthouse/Ebsar courses to date, and the regional infrastructure has been enhanced because adjunct faculty has the ability to respond to the training needs of hospital staff. What does the future hold for training in low vision care? Growth. In addition to the increased demand for services caused by the aging of our population, several other factors are increasing professionals' desire to learn more about this specialized area of practice. One is the potential of a positive outcome of the current Centers for Medicare and Medicaid demonstration project regarding national Medicare coverage in the United States. Another is the heightened need for cross training as professionals with other specialties (such as occupational therapy) seek to add aspects of low vision care to their skill set. Lastly, there is a growing international awareness of the economic impact of failing to provide low vision care. Now, as in the past, continuing education and training are vital to stimulating the availability of these essential services for people in need. Karen R. Seidman, MPA, is Vice President for Continuing Education and International Program Development at Lighthouse International. (Callout) There is a growing international awareness of the economic impact of failing to provide low vision care. Optic Nerve Protection and Regeneration After Disease and Injury by Kin-Sang Cho, PhD, and Dong Feng Chen, PhD Optic Nerve Disease and Damage Retinal ganglion cells (RGCs) are a unique cell population in the retina that send long nerve fibers -- collectively, they form the optic nerve -- and convey visual information to the brain. Once the optic nerve is damaged due to trauma or disease, such as glaucoma or optic neuritis, the transmission of the visual signal from the eye to the brain is impaired. Such damage is usually irreversible and eventually can lead to blindness. About 2.2 million Americans have glaucoma, and about 120,000 are blind. So far, treatment for optic nerve diseases or damage is very limited. Therefore, understanding the mechanisms that control optic nerve regeneration may lead to therapeutic strategies that can reverse the fate of optic nerve injury or degeneration. Unlike neurons in the peripheral nervous system (PNS), which retain the ability to regenerate after injury, neurons in the central nervous system (CNS) of mammals, including the brain, spinal cord and retina/optic nerve, normally cannot regenerate once damaged. Accumulating evidence now suggests two barriers that stand in the way of optic nerve regeneration: the internal barrier created by intrinsic properties of a mature neuron and the outer barrier created by external environment surrounding the neuron. External Constraints for Optic Nerve Regeneration Almost two decades ago, Aguayo and co-workers demonstrated elegantly that the discrepancy between the regenerative potential of CNS and PNS neurons after injury could be, at least in part, attributed by the different microenvironment in their nerves. When a piece of sciatic nerve, which presents a PNS microenvironment, was transplanted to connect with an injured optic nerve, it induced some regeneration from the nerve;1 some even reached the brain target, the superior colliculus, and formed synapses.2 These findings once raised hopes that optic nerve regeneration may become reality if the CNS environment can be changed to support nerve re-growth. Years of the following, searching for molecules that could turn the CNS into a growth-permissive environment, became the main themes in the field of optic nerve regeneration. 1. Neurotrophic factors The ability of an injured neuron to recover from injury in adulthood may be influenced by signals that also determine their fate in development. Neurotrophic factors are one of such signals that promote neuronal survival and neurite growth. NGF was the first characterized target-derived survival factor for developing sympathetic and sensory neurons. It is now clear that it also plays an important role in the maintenance and regeneration of mature peripheral neurons. It has been long thought that inadequate supply of neurotrophic factors in the adult CNS may contribute to the failure of optic nerve regeneration. However, although most neurotrophic factors stimulate neurite outgrowth in vitro, they are less effective on doing so in vivo.3 Ciliary neurotrophic factor, nevertheless, appears to give rise the best result on enhancing optic nerve regeneration when it is provided intravitreally or delivered using lentiviral vector.4-7 2. Myelin and formation of glial scars Besides inadequate supply of nerve growth-stimulating factors, mature CNS is also thought to present inhibitors, primarily those associated with myelin and astrocytic scars, to actively prevent optic nerve regeneration. A major advance in the last decade that studies the mechanisms of CNS inhibition has been the molecular cloning of myelin- associated inhibitor Nogo8 and the receptor NgR.9 In addition to Nogo, at least two other proteins, myelin-associated glycoprotein (MAG)10, 11 and oligodendrocyte-myelin glycoprotein,12 have been identified that can also cause axon growth inhibition. Neutralizing antibody against CNS myelin preparation or Nogo, mainly IN-1, has been shown to induce slow regeneration of certain spinal axons;13, 14 however, application of IN-1 did not improve optic nerve regeneration.15 Interestingly, recent reports using genetic mouse models that disrupt myelin-dependent growth inhibition by knocking out MAG,16 Nogo17-19 or their common receptors and co-receptors18, 20, 21 results in only minimal improvement of regeneration. This suggests that myelin inhibitors may not be the only players contributing to the failure of CNS regeneration. Astrocytic scar is identified as a responsive process by astrocytes, characterized by astrocyte proliferation and up-regulation of intermediate filaments following traumatic injury to the CNS. Formation of astrocytic scar presents another obstacle for optic nerve regeneration. Extracellular matrix molecules produced by astrocytic scars, including many proteoglycans, particularly chondriotin sulfate proteoglycan (CSPG), have been suggested to repel axon regeneration.22 Depletion of CSPG around the injury site by inhibiting its synthesis or promoting the degradation led to improvement of axon regeneration in the spinal cord.23-25 Compelling evidence now indicates that activation of protein kinase C and RhoA may be a convergent point of various inhibitory signals induced by myelin and CSPG.26, 27 Inhibition of RhoA stimulates optic nerve regeneration in adult mice.28 Moreover, high level of cAMP and activation of its down stream signal cAMP response element binding protein enhances neurons' ability to overcome myelin inhibition and promotes optic nerve regeneration.29, 30 These studies point to new promising therapeutic avenues for enhancing optic nerve regeneration. Intrinsic Determinants Manipulating the external environment improves modest, if any, CNS regeneration. Current prevailing views are that the failure of optic nerve regeneration is attributed not only to environmental constraints, but also the intrinsic incompetence of mature RGC axons.31 Proteins known to regulate axon growth potential include GAP-43,32 Bcl-2,33- 35 cAMP,36 microphage-activated factor.37 It has been shown that lens injury activates macrophage38 and induces optic nerve regeneration in adult mice.38, 39 Most strikingly, Bcl-2, a protein that inhibits cell death, has been identified as one of the intrinsic factors that control optic nerve regeneration and are lost by mature RGCs.33, 35 Mice overexpressing Bcl-2 can regrow their optic nerve, if the injury is incurred within three days after birth, a time when the CNS environment remains permissive for such growth.34 Our recent study reports that astrocytes mature and acquire the ability to form scars around injury after postnatal day four, correlating with the timing of optic nerve regenerative failure in Bcl-2 overexpressing mice. To determine whether removing scars could release the brakes on optic nerve regeneration in Bcl-2 overexpressing mice, we created mice that not only overexpressed Bcl-2, but also lacked two proteins involved in scar formation -- glial fibrillary acidic protein and vimentin. With this combination of factors, the optic nerve regeneration was restored, growing rapidly and innervating the brain visual targets in just a few days.34 However, the regenerative ability of the mice was only sustained up to two weeks of age, at a time when myelin begins to develop. It suggests that development of myelin may contribute to additional inhibition for optic nerve regeneration after two weeks of age. Thus, future studies that improve the CNS environment for regeneration should target both astrocytic scars and myelin. Conclusion Altogether, the data suggest that controlling either intrinsic or extrinsic factor(s) alone is not sufficient to restore the regenerative capacity of an injured optic nerve in the adult. A combined strategy that manipulates both may become a trend for promoting optic nerve regeneration and repair. Finding ways to regulate gene expression or maneuver intracellular signaling events, without genetic manipulation, will be the next important step toward development of therapy for optic nerve disease and injury. References 1. David, S. & Aguayo, A. J. (1981). Axonal elongation into peripheral nervous system "bridges" after central nervous system injury in adult rats. Science, 214(4523), 931-3. 2. Carter, D. A., Bray, G. M., Aguayo, A. J. (1989). Regenerated retinal ganglion cell axons can form well-differentiated synapses in the superior colliculus of adult hamsters. Journal of Neuroscience, 9(11), 4042-50. 3. Cui, Q., So, K. F., Yip, H. K. (1998). 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Lentiviral-mediated transfer of CNTF to schwann cells within reconstructed peripheral nerve grafts enhances adult retinal ganglion cell survival and axonal regeneration. Molecular Therapy, 11(6), 906-15. 8. Chen, M. S., Huber, A. B., van der Haar, M. E., et al. (2000). Nogo-A is a myelin- associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature, 403(6768), 434-9. 9. Fournier, A. E., GrandPre, T., Strittmatter, S. M. (2001). Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature, 409(6818), 341-6. 10. McKerracher, L., David, S., Jackson, D. L., et al. (1994). Identification of myelin- associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron, 13(4), 805-11. 11. Mukhopadhyay, G., Doherty, P., Walsh, F. S., et al. (1994). A novel role for myelin- associated glycoprotein as an inhibitor of axonal regeneration. Neuron, 3(3), 757-67. 12. Wang, K. C., Koprivica, V., Kim, J. A., et al. (2002). 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A role for cAMP in regeneration of the adult mammalian CNS. Journal of Anatomy, 204(1), 49-55. 37. Schwartz, M.,Yoles, E. (2005). Macrophages and dendritic cells treatment of spinal cord injury: from the bench to the clinic. Acta neurochirurgica: Supplementum, 93,147- 50. 38. Fischer, D., Pavlidis, M., Thanos, S. (2000). Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Investigative Ophthalmology & Visual Science, 41(12), 3943-54. 39. Leon, S., Yin, Y., Nguyen, J., et al. (2000). Lens injury stimulates axon regeneration in the mature rat optic nerve. Journal of Neuroscience, 20(12), 4615-26. Aging&Vision Cynthia Stuen, DSW/PhD, Senior Vice President for Education, and Vision Rehabilitation Programs Laurie A. Silbersweig Director of Editorial Services Photos: Dorothea Anne Lombardo, Peter Vidor Aging & Vision Editorial Board Cynthia Stuen, DSW/PhD, Chair Aries Arditi, PhD Eleanor E. Faye, MD, FACS Michael Fischer, OD, FAAO Kent Higgins, PhD Amy Horowitz, DSW Bruce Rosenthal, OD, FAAO Carol Sussman-Skalka, CSW, MBA This newsletter is available in alternate formats and on our Web site: www.lighthouse.org. Lighthouse International Tara A. Cortes, RN, PhD President and CEO Lighthouse International is a leading resource worldwide on vision impairment and vision rehabilitation. Through its pioneering work in vision rehabilitation services, education, research, prevention and advocacy, Lighthouse International enables people of all ages who are blind or partially sighted to lead independent and productive lives. Founded in 1905 and headquartered in New York, Lighthouse International is a not-for-profit organization, and depends on the support and generosity of individuals, foundations and corporations. 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