Applied Genetic Technologies, the University of Massachusetts Medical School, the Oregon Health & Science University and the Foundation Fighting Blindness Announce Open Recruitment for a Phase 1/Phase 2 Research Clinical Trial
A Multiple-Site, Phase 1/2, Safety and Efficacy Trial of a Recombinant
Adeno-associated Virus Vector Expressing RPE65 (rAAV2-CB-hRPE65) in Patients with
Leber Congenital Amaurosis Type 2
Applied Genetic Technologies Corporation is the gene therapy development company providing the study drug and is the sponsor of this research trial. The University of Massachusetts , Worcester , MA (docket #H-13062) and the Casey Eye Institute at the Oregon Health & Science University , Portland , OR (eIRB# 4892) are the two clinical sites for this study. You are receiving this information from the Foundation For Rental Research (FRR) because you have indicated that you are a health care provider for retinal degenerative disease or that you or someone in your family is affected by Leber Congenital Amaurosis (LCA).
Leber Congenital Amaurosis is an inherited, blinding eye disease for which there is currently no treatment. Mutations in as many as 13 different genes can cause LCA; one of those is the RPE65 gene.
The RPE 65 gene makes the RPE65 protein that is needed for the retina to work normally. The study drug contains a normal copy of the RPE65 gene and also contains part of a virus called AAV. The AAV virus does not cause illness in humans, and it is used in the study drug to help the normal RPE65 gene get into cells of the retina after an eye surgeon injects the study drug beneath the retina in the back of one eye.
The purpose of this research study is to test whether the study drug, called rAAV-CB-hRPE65, is safe and to see if it can improve vision in individuals who have a mutation in their RPE65 gene. Right now, rAAV-CB-hRPE65, is not approved by the United States Food and Drug Administration (FDA) to treat people with changes in their RPE65 genes because not enough is known about the drug. The FDA will allow testing of the drug only in a research study such as this one.
Individuals may have a diagnosis of LCA but may not know whether or not it is caused by the RPE65 gene. These individuals may contact one of the investigators (contact info on back) who will ask a few screening questions over the phone. If the results of the phone interview indicate a possible RPE65 mutation, the individual may be asked to have a blood sample sent to a laboratory for confirmation. If testing of the blood sample reveals an RPE65 mutation as the cause of the LCA, the individual may be asked to travel to a study site to have additional evaluation and tests performed.
Potential participants will be asked to come to one of the two clinical sites. If their home is not close to the site, they will have to stay at a nearby hotel. During the first visit, there will be examinations and tests done to see if the individual is eligible to join the study. At the second visit, there will be more tests and if these results are acceptable, the participant will receive the study drug two days later. An eye surgeon will inject the study drug beneath the retina in one eye only.
After receiving the study drug, participants will be examined and have tests performed 1, 7 and 14 days later and then again at 1, 2, 3, 6, 9, 12, 18, and 24 months. Patients are expected to travel to the site where the injection was done for each of these visits, since special equipment is used to measure their visual function. After the 24-month visit, they will be contacted once a year for 15 years and asked to answer questions. They will also be asked to have a follow-up visit once a year from years 3 to 15 after treatment. These follow-up visits can be performed by their local ophthalmologist.
Participants are not paid for being in the study. However, participants will be reimbursed for reasonable costs related to the travel to attend the initial evaluation visit and, if accepted into the study, subsequent study visits.
Some of the basic criteria for inclusion or exclusion in this trial are as follows:
Inclusion Criteria:
Retina disease consistent with a diagnosis of Leber Congenital Amaurosis caused by a documented mutation in the RPE65 gene;
- At least 8 years of age;
- Good general health;
- Able to perform tests of visual and retinal function;
- Visual acuity not better than 20/60 and not worse than light perception in both the treated eye and the fellow eye
Exclusion Criteria
- Pre-existing eye conditions that would preclude the planned surgery or interfere with interpretation of study endpoints or complications of surgery (e.g. glaucoma, corneal or lenticular opacities or history of retinal detachment)
- History of immunodeficiency or other medical conditions that might increase the risk of study drug (rAAV2-CB-hRPE65) administration;
- Use of anticoagulants or anti-platelet agents within 7 days prior to study agent administration
- History of allergy or sensitivity to medications planned for use in the peri-operative period;
- Use of any investigational agent or systemic corticosteroids or other immunosuppressive drug(s) within 3 months prior to enrollment.
Additional and detailed inclusion and exclusion criteria can be reviewed at http://www.clinicaltrials.gov/. Study identifier is NCT00749957. Questions regarding criteria for possible participation can also be directed to the investigators at either University of Massachusetts or Casey Eye Institute.
University of Massachusetts Medical School
Worcester, Massachusetts , United States, 01605
Contact: Principal Investigator- Shalesh Kaushal, MD, PhD - 508-334-0687
Shalesh.Kaushal@umassmemorial.org
Contact: Margaret Humphries, RN - (508) 856-5711 Margaret.Humphries@umassmed.edu
Casey Eye Institute, Oregon Health & Science University Portland, Oregon, United States, 97239 Contact: Principal Investigator- J Timothy Stout, MD, PhD, MBA - 503-494-2435 - stoutt@ohsu.edu
Contact: Peter Francis, MD, PhD - (503) 494-8386 - francisp@ohsu.edu
Contact: Maureen Toomey, BS (503) 494-3795 - toomeym@ohsu.edu
Applied Genetic Technologies Corporation http://www.agtc.com/
Foundation For Retinal Research http://www.tfrr.org/
The FRR is providing this notification for informational purposes only. Any interested parties must make arrangements directly with the principal investigators who are responsible for the conduct of this research. The FRR makes no representations regarding the safety, efficacy or research results of the project. If you choose to participate in this study, you should do so only after careful consideration on your part and without reliance in any way upon the FRR. You may consult your own physician in deciding whether to participate in the study. The FRR is not legally responsible for or to any person who decides to participate in the study
Helping the blind to see?
With some types of blindness, such as macular degeneration and proliferative retinal diseases, a scanning laser ophthalmoscope (SLO) may be the key to a “seeing machine”.
A portable device, based on the concept of the SLO, was developed that allows “people with visual impairments to watch videos, access the internet, view photographs, or just see the face of a friend.”
This device is the result of the work by Elizabeth Goldring, a senior fellow at MIT’s Center for Advanced Visual Studies, and her team. When Goldring lost vision in both her eyes, she went to Schepens Eye Research Institute in Boston where they used an SLO to test her retinas. As reported in the recent article in PC World magazine, the SLO could bypass the hemorrhages that contributed to her blindness and project images directly onto the retina of the eye. Goldring was able to see the figures projected by the technician.
This is all at the prototype stage right now, but you must start somewhere! Goldring’s team aims to reduce the cost of such a device. When an SLO costs USD 100,000, they won’t be the top selling item in your local electronics store! For now, the price in the MIT team’s portable device is down to USD 500, and they plan to test the machine outside the laboratory soon.
Good luck to the team!
PC World magazine article
Seeing Machine Helps Blind A seeing machine developed at MIT helps people with visual impairments
Nick Barber, IDG News Service
Friday, January 23, 2009 12:00 PM PST
Using her prototype "seeing machine," Elizabeth Goldring can take pictures and see them -- with her blind eye.
After more than 20 years of work, Goldring, a senior fellow at MIT's Center for Advanced Visual Studies and her colleagues have designed a portable device that allows people with visual impairments to watch videos, access the internet, view photographs, or just see the face of a friend.
Her work started when she lost the vision in both of her eyes and doctors at the Schepens Eye Research Institute in Boston used a scanning laser ophthalmoscope, or SLO, to determine if she had any healthy retina left. The machine, which costs over US$100,000, projected images directly onto the retina of the eye, bypassing the hemorrhages contributing to her blindness. "Technicians projected stick figures onto my retinas and I could see some of those stick figures," she said of the experience. Goldring then asked them if they could write the word "sun," which she could also see. "I was amazed. It was the first word I'd seen for months." After her visit, she contacted and worked with the inventor of the SLO, hoping to reduce the size and cost of the device. That research yielded a $4,000 desktop model that allowed the blind to see black-and-white images. Soon after, a desktop model was created that allowed for color images to be seen. Goldring admits that version doesn't work well, but it paved the way for the current prototype.
Once a video signal is plugged into the 5-inch square box, it is then fed to an LCD panel on the inside, according to Quinn Smithwick, a postdoctoral associate at the MIT Media who has been working with Goldring on the seeing machine. The connection to the box is for a standard RCA video jack so almost anything with a video output can be plugged in. The LCD panel inside is illuminated by a bright bank of LEDs behind it, which are collimated, or traveling in the same direction. As the light passes through the LCD screen, the image pattern is "imprinted" onto the light. A lens at the back of the box focuses the light into a single point, which then enters the pupil of the eye and passes onto the retina.
"It's not that we're taking the camera image and blowing it up so you can see something big," said Smithwick. "We're trying to bypass any bad optics you may have and then get enough light and enough contrast onto the back of your retina and then you can use what little bits of retina you may have left to view it."
Goldring thinks the seeing machine could help people with macular degeneration and proliferative retinal diseases, two of the main causes of blindness in the U.S. , according to Goldring. Using the device, Goldring said she can see faces and general details of people such as the color of their hair and what they are wearing. Without it, she would only know that someone is standing close to her.
Brandon Taylor, a graduate student at the MIT Media Lab, said the next step for the seeing machine is to test it with a wider population. "We've received positive results with Elizabeth and there have been a couple other people who have used it and its been very encouraging, but what we really want to do for this testing phase is figure out what types of eye conditions this is beneficial for ... and how much improvement this machine can achieve," said Taylor. Goldring noted that there does need to be some working retina for the machine to work. "People aren't interested in what blind people see and we have a lot of pent-up desire to express ourselves visually and this is the first step to that," said Goldring. She and her team already have plans under way to test the seeing machine at the Low Vision Clinic at the Joslin Diabetes Center 's Beetham Eye Institute in Boston . After refining the device, they would also like to make it commercially available, though are not sure when it will be or for how much. Their prototype, not including the digital camera, cost under $500 because "everything in it is already mass-produced for other purposes," Taylor said.
"Keeping the visual sense alive is something good, even if you don't use it to cross the street," Goldring said.
Stem cells ready for prime time, Published online January 27, 2009
US regulatory agency gives the go-ahead for first clinical trials of a human embryonic stem-cell treatment.
Meredith Wadman
It was a triumph of science, not politics. Yet the approval for the world's first clinical trial of a therapy generated by human embryonic stem cells, announced on 23 January, certainly seemed to be deeply political.
It was just three days into US President Barack Obama's term of office when Geron, based in Menlo Park , California , told the world that the US Food and Drug Administration (FDA) had agreed to its phase I safety study of a stem-cell-derived therapy for spinal-cord injury. But supporters say that the significance of the approval lies not in the ideology of the new administration, but in the considerable scientific hurdles that were overcome in reaching this milestone. "There was a lot of scepticism as to whether we could reliably reproduce these manufactured products at levels of purity and identity sufficient to even allow the FDA to allow a phase I clinical trial," says Michael West, who founded Geron in 1990 and is now chief executive of BioTime in Alameda , California . Geron, he says, "has convinced the FDA that those cells could be manufactured reliably enough for at least the first clinical trials. That is a milestone. A lot of the critics said it would be 30–50 years before we got there."
Financial benefit
The announcement boosted the price of shares in the company, which has an extensive patent portfolio relating to embryonic stem-cell research. As of 26 January, they were trading at US$8.15 a share — up 56% from the day before the announcement. In the trial, up to ten individuals who have been left paralysed after spinal-cord injury will be injected at the point of injury with stem-cell-derived precursors of oligodendrocytes, which are key supportive cells in the central nervous system. The treatments will start within 7–14 days of their injury. The company hopes that the cells will lay down sheaths of myelin — an insulator essential for conducting nerve impulses — around injured neurons, as well as stimulating nerve cells to regenerate. The cells have demonstrated both capabilities in animals (H. Keirstead et al. J. Neurosci. 25, 4694–4705; 2005). Geron says that it expects to begin enrolment early this summer at up to seven US medical centres. In a conference call with analysts and reporters, the firm's president and chief executive Thomas Okarma said that the trial "marks the dawn of a new era in medical therapeutics. This approach is one that reaches beyond pills and scalpels to achieve a new level of healing."
“This is a trial of one particular application, not a trial of all embryonic stem cells.” Geron's 22,000-page FDA application was first submitted in March 2008, at a time when President George W. Bush had placed tight restrictions on federal funding for embryonic stem-cell research. Although Obama has promised to reverse those restrictions, the company and the FDA deny that any politics were at play in the timing of the announcement. "Science drives our decision-making," says Karen Riley, an FDA spokeswoman. "Political considerations have no role in this process." Riley adds that the process was prolonged by the time it took Geron to respond to additional questions the FDA asked the company last spring after receiving the application. Okarma says that the application included data from more than 24 studies, involving nearly 2,000 animals with injured spinal cords and requiring the production and injection of more than 5 billion cells. Indeed, the Geron cells come from one of a score of lines approved for federal funding under the Bush policy.
Groups opposing such research say that the trial's risks include the growth of tumours. "The ethical concerns include both using human embryos for the experiment as the source material, but also concern for the patient," says David Prentice, senior fellow for life sciences at the Family Research Council, a Christian advocacy group in Washington DC . "This is not a life-threatening condition," he says. "Are you actually going to be shortening the patient's life?" He cites a 2006 study in which some neural support cells — derived from human embryonic stem cells — reverted to undifferentiated growth when injected in rat models of Parkinson's disease (N. S. Roy. et al. Nature Med. 12, 1259–1268; 2006).
Not perfect, but timely Supporters of stem-cell research have praised the FDA approval, saying that there is no 'perfect' trial with which to begin. "What I care about, what investors care about, what people who are debilitated care about, is something that can happen in the near future — not a perfect product two generations from now," says Steve Brozak, president of investment company WBB Securities in Westfield, New Jersey. Brozak has tracked stem-cell research since James Thomson, a researcher at the University of Wisconsin in Madison , published his work on the first successful isolation of human embryonic stem-cell lines in 1998. Other advocates say the trial should not become a test case on which the fortunes of the entire field rise or fall. "This is a trial of one particular application, not a trial of all embryonic stem cells," says Sean Tipton, immediate past-president of the Coalition for the Advancement of Medical Research in Washington DC . Geron is a big fish in what is currently a very small pond. The other high-profile company in the field, Advanced Cell Technology in Los Angeles , California , was recently on the brink of bankruptcy. And Novocell in San Diego , is working to develop human embryonic stem cells into pancreatic β-cells, which produce insulin. Although diabetes provides a huge treatment target, Novocell's project is daunting because of the technical challenges involved in producing β-cells that safely mediate blood-sugar levels.
January 2009
Gene Therapy in a New Light
http://www.smithsonianmag.com/science-nature/Gene-Therapy-in-a-New-Light.html
November 2008
Youngest patient to have new surgery has improving vision http://www.dailygazette.com/news/2008/nov/02/1102_blindboy/
December 2008
Multidisciplinary Team Researching Gene Therapy For Human Degenerative Retinal Diseases
A Canadian and American research group including the team of Dr. Robert Koenekoop from the Research Institute at the Montreal Children's Hospital of the MUHC has just been awarded $2.4 million from the Canadian Institutes of Health Research (CIHR) and the Foundation Fighting Blindness Canada (FFB). This five-year grant will fund an ambitious research project to develop innovative gene therapies for a number of human degenerative retinal diseases.
A multidisciplinary and complementary team
The complementary skills of the five research teams involved will provide the multidisciplinarity required for success in this research project. The project will be led by Dr. Robert Molday, a cell biologist from the University of British Columbia . The team's other experts in gene therapy are Dr. Jim Hu from the University of Toronto , and Dr. Bill Hauswirth from the University of Florida . Dr. Marinko Sarunic of Simon Fraser University will be responsible for the retinal imaging component of the project.
As the team's clinician-scientist, Dr. Robert Koenekoop will oversee the visual function testing and the gene analyses, first in animals and then in humans with a variety of retinal degenerations. After several years of testing in animals, human patients will be injected with the "new healthy gene" that aims to partially restore vision.
Innovative gene therapies
"We hope to begin a human gene-therapy trial in Canada within five years for three specific degenerative retinal diseases: Leber Congenital Amaurosis (LCA), Stargardt macular dystrophy and retinitis pigmentosa," Dr. Koenekoop explained. "Previous attempts with the gene named RPE65 have been highly conclusive for LCA: we believe that we can learn from that and advance even more quickly this time. It's very motivating!"
RPE65 mutations are one cause of Leber Congenital Amaurosis. Three independent research teams have very recently shown that injecting a healthy version of that gene to young adults can partially restore their vision.
The CIHR's Regenerative Medicine and Nanomedicine Initiative
Nine projects were awarded grants through the CIHR program entitled "Regenerative Medicine and Nanomedicine - Emerging Team Grants - July 2008." All of these projects hold great hope for medical applications in the fields of nanotechnology, stem cells, tissue engineering and rehabilitative sciences.
To receive the grant, the team had to show a multidisciplinary commitment to addressing problems in regenerative medicine. The long-term goal of this program is to develop innovative treatments that are scientifically based and socially validated.
Dr. Robert Koenekoop is the Director of the Division of Pediatric Ophthalmology and the McGill Ocular Genetics Laboratory at the Montreal Children's Hospital of the MUHC. He is a researcher in medical genetics and genomics with the Research Institute at the Montreal Children's Hospital of the MUHC. Dr. Koenekoop is an Associate Professor in Human Genetics and Ophthalmology in the Faculty of Medicine at McGill University . His research is also funded by the Foundation Fighting Blindness Canada and the Fonds de la recherche en santé du Québec (FRSQ).
Article adapted by Medical News Today from original press release.
The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal , Quebec , the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University . The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.
The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santé du Québec. For further details visit: http://www.muhc.ca/research.
Find this press release, with the original article and a short audio document by following this link : http://www.muhc.ca/media/news/
This release is available in French.
Source: Isabelle Kling McGill
University Health Centre Article URL: http://www.medicalnewstoday.com/articles/131739.php
Ikaros Confers Early Temporal Competence to Mouse Retinal Progenitor Cells
Jimmy Elliott, Christine Jolicoeur, Vasanth Ramamurthy, Michel Cayouette
Neuron Volume 60, Issue 1, Pages 26-39 (9 October 2008)
Summary
In the developing mouse retina, multipotent retinal progenitor cells (RPCs) give rise to specific retinal cell types at different times, but the molecular mechanisms regulating how RPCs change over time remain unclear. In the Drosophila neuroblast lineage, the zinc finger transcription factor Hunchback (Hb) is both necessary and sufficient to specify early-born neuronal identity. We show here that Ikaros, a mouse ortholog of Hb, is expressed in all early embryonic RPCs, which then give rise to Ikaros-negative RPCs at later stages in the lineage. Remarkably, misexpression of Ikaros in late RPCs is sufficient to confer competence to generate early-born neurons. Conversely, Ikaros mutant mice have reduced numbers of early-born cell types, whereas late-born cell types are not affected. These results suggest a model in which Ikaros expression is both necessary and sufficient to confer early temporal competence to RPCs and raise the possibility that a similar strategy might be used to control the sequential order of cell birth in other parts of the nervous system.
Second Sight Expands International Clinical Trial for Argus II Retinal Implant
First Retinal Prosthesis Study of its Kind Seeks to Partially Restore Vision to the Blind
LAUSANNE, Switzerland, Nov 19, 2008 (BUSINESS WIRE) -- Second Sight(R) Medical Products, Inc., the leading developer of retinal prostheses for the blind, announced that it will increase patient enrollment for the Argus(TM) II Retinal Implant study throughout clinical trials sites within Europe. The three-year feasibility study is currently underway in the United States , Europe and Mexico for people with Retinitis Pigmentosa (RP), a genetic eye disease that causes blindness.
"We are encouraged by the results we have seen in the seventeen individuals that have participated in the study so far," said Robert Greenberg, MD, PhD, President and CEO of Second Sight. "We are now expanding our trial enrollment in order to strengthen our data, further demonstrate clinically meaningful performance and begin the process of seeking market approval."
Retinal Prostheses are currently the only devices being studied to provide some sight to subjects blinded from outer retinal degenerations, such as advanced RP. Second Sight conducted its first proof-of-concept clinical study in early 2002 at Doheny Eye Institute at the University of Southern California (USC) in Los Angeles . During that study, six RP volunteers were implanted with the Argus I system and many continue to use it at home for several hours each day.
The Argus II, the latest device being studied in the clinical trial, is the second generation Retinal Prosthesis that consists of a 60-electrode grid that is surgically implanted on the retina. These electrodes transmit information acquired from an external video camera that is mounted on a pair of eyeglasses worn by implanted subjects. The implant has been designed to last a lifetime, but can safely be removed if necessary.
Preliminary results from the Argus II feasibility study were presented last month at the American Society of Retinal Specialists (ASRS) in Hawaii . According to Mark Humayun, MD, PhD, Professor of Ophthalmology at the Doheny Eye Institute at USC, there were no device failures and few serious adverse events occurred in the 17 subjects that have been enrolled in the study for an average of 14 months, the most serious of which resulted in removal of an implant without difficulty or harm to the individual.
Additionally, Dr. Greenberg reported on the orientation and mobility performance observed in the first 11 study volunteers. Using Second Sight's Argus II system, these individuals were frequently able to locate a door up to 20 feet away and walk to the end of a 20 foot line drawn on the floor.
Internationally, three major European centers are participating in the feasibility study, including Service d'Ophtalmologie, HA'pital Cantonal Universitaire de Geneve in Geneva , Le Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts in Paris , and Moorfields Eye Hospital in London . Second Sight continues to enroll subjects at these centers and may establish additional clinical trial centers in Europe . Furthermore, the company has made additional improvements to the Argus II system that may increase its clinical benefits.
"These first results hold a novel and quite unprecedented promise for blind subjects as well as the physicians and researchers that have the opportunity to participate in this pioneering endeavor," commented Jose-Alain Sahel, MD, Principal Investigator and Chairman, Department of Ophthalmology, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris. "We now have a strong incentive for continuing and expanding the efforts in testing this new technology."
Four leading ophthalmic centers throughout the U.S. have enrolled subjects in the study to date, including Doheny Eye Institute at the University of Southern California (USC) in Los Angeles , CA , Wilmer Eye Institute at Johns Hopkins University in Baltimore , MD , the University of California at San Francisco and the Retina Foundation of the Southwest in Dallas , TX . Second Sight is currently seeking permission from the US Food and Drug Administration to further expand the U.S. trial. The study is also being conducted at Centro de Retina Medica y Quirurgica , SC , Centro Medico Puerta de Hierro, CUCS and Universidad de Guadalajara in Guadalajara , Mexico .
"Retina International and its members in more than 40 countries are excited that this innovative research is now in critical clinical trials and that it is bringing hope to thousands of people with advanced retinal disease," says Christina Fasser, President of Retina International and CEO of Retina Switzerland. The British Retinitis Pigmentosa Society, Retina France, the Federation des Aveugles de France and the Fondation Ophtalmologique Rothschild have been similarly supportive in Europe .
The development of this technology was largely supported by the National Eye Institute (NEI) of the National Institutes of Health (NIH), and the Department of Energy's Office of Science (DOE) Artificial Retina Project, which is helping to advance the implant's design and construction.
If you would like to learn more about the Argus II international feasibility study, please contact Second Sight at info@2-sight.com or +41 21 693 91 51 (Europe), (818) 833-5027 (US).
About Second Sight
Second Sight(R) Medical Products, Inc., located in Sylmar , Calif. , is a privately held company founded in 1998 by Alfred Mann and others with the goal of creating a retinal prosthesis to provide sight to subjects blinded from outer retinal degenerations, such as Retinitis Pigmentosa. Through dedication and innovation, Second Sight's mission is to develop, manufacture and market implantable visual prosthetics to enable blind individuals to overcome their disability and achieve greater independence. The company has received extensive U.S. federal support in developing this new technology and is grateful for the forward thinking of the National Institutes of Health/National Eye Institute and the Office of Science at the Department of Energy in supporting significant aspects of this work. For more see http://www.2-sight.com/.
This press release contains forward-looking statements. Second Sight Medical Products wishes to caution the reader that actual results may differ from those discussed in the forward-looking statements, and may be adversely affected by, among other things, risks associated with new product development and commercialization, clinical trials, regulatory approvals, reimbursement, and other factors. Second Sight is a registered trademark and Argus is a trademark of Second Sight Medical Products, Inc.
SOURCE: Second Sight Medical Products, Inc.
Testing of Children Newly Diagnosed with Leber’s Congenital Amaurosis (LCA)
LCA is a hereditary retinal degeneration (RD) whose primary clinical manifestation (phenotype) is significant and early visual impairment. It is part of a larger family of retinal degenerations collectively called Retinitis Pigmentosa all of which lead to degeneration of the photoreceptor cells of the retina.
However, in some cases, other disease processes (another specific retinal degenerative condition, infection, etc.) can result in symptoms close to those of true hereditary LCA and lead to a misdiagnosis. Thus, a careful screening is needed if LCA is suspected in a young child to rule out other diseases with similar symptoms.
In a somewhat similar manner, LCA is occasionally associated with problems other than in the visual system. Therefore, a series of tests is sometimes warranted to make sure that other functions (hearing, cognitive ability, kidney function, etc) are not also affected.
A) Initial Examination In a thorough exam, the following tests should be considered with final correlation through the Ophthalmologist:
1) Physical Exam: A complete physical exam conducted usually by the primary care physician to rule out other medical issues as best as possible. Particular attention should be paid to muscle tone, kidney function and breathing pattern (see section C below).
2) Hearing Test: A hearing test should be done in early onset retinal degenerations. Early hearing loss with early vision loss may indicate Usher Syndrome, a hereditary condition in which hearing as well as vision is impaired, instead of LCA.
B) Ruling Out Other Conditions: As mentioned above, some conditions initially mimic the physical signs of LCA.
1) Refsum’s Disease: Refsum’s Disease is a very rare hereditary condition in which there is an inability in the patient to break down (metabolize) a substance called phytanic acid. Phytanic acid is found in most foods of plant origin. In affected patients, the metabolizing enzyme is missing so there is a large buildup of phytanic acid in the body and ensuing tissue damage. In the retina, early vision loss and night blindness are observed – classical signs shared by Retinitis Pigmentosa and LCA. Clinical gene testing can be done on a small sample of blood since the gene defect is known.
2) Batten’s Disease: Batten’s Disease is a rare, inherited degenerative disorder that affects the retina as well as nerve cells in brain and peripheral parts of the body. Visual problems are seen as an early symptom but these are usually accompanied by other problems in cognitive and motor abilities. Clinical gene testing can be done on a small blood sample since, as with Refsum’s Disease, the causative gene mutation is known.
3) Infection: Many infections acquired during pregnancy can negatively affect function in the newborn including in the visual system, hearing, etc. Testing for such infections is often called a “TORCH Screening”. TORCH is an acronym for a grouping of infections that include: Toxoplasmosis Other infections (Syphilis, Hepatitis B, Herpes Zoster) Rubella Cytomegalovirus (CMV) Herpes simplex Infection by one or more of these agents can sometimes masquerade as a hereditary retinal degeneration such as LCA since they are congenital and have many of the same phenotypic characteristics. Testing is simple and direct using a small blood sample. Antibodies to the various infectious gents are specific and reliable and can be used to test the blood sample for the presence of the pathogen.
C) Syndromes that can include LCA Some gene defects lead to malfunctioning in more than one organ of the body as in Usher Syndrome (US). In the case of US, the gene mutations can lead to dysfunction of what are known as “ciliated cells” which are critical in such diverse functions as hearing, vision and kidney function. Though not often fully appreciated then, kidney function should be evaluated in some way in cases of LCA.
1) Usher Syndrome In Usher Syndrome, there is a loss of hearing as well as vision problems. Symptoms can be severe (Type 1), moderate (Type 2) or mild (Type 3). In both the retina and the ear, specific cells are ciliated (i.e., contain a specific structure called a cilium) that act a sensory cells. If the genetic mutation affects function of the cilium, it can do so in both the eye and ear and lead to hearing and vision problems.
2) Joubert Syndrome (JS) Joubert Syndrome is due to underdevelopment of an area of the brain. It usually results in a number of problems for the child including poor muscle control (ataxia) and abnormal breathing (hyperpnea). Kidney and liver problems can be present so function of these organs needs to be tested if JS is suspected. In many cases, JS is accompanied by eye problems that are similar or identical to those seen in LCA. In fact, some of the same genes can be affected in the two conditions.
3) Senior-Loken Syndrome (SLS) SLS is a rare disease is which problems are seen in many tissues and organs of the body. Kidney problems (nephronophthisis) can be severe and lead to kidney failure. Retinal degeneration is also seen as in LCA or Retinitis Pigmentosa. Other problems such as mental retardation and hypertension can be encountered. SLS has recently been included in diseases called “ciliopathies”, i.e., diseases that affected cells containing a cilium.
4) Alstrom Syndrome (AS) Alstrom Syndrome is a very rare condition that can affect many organs of the body. It affects both hearing and vision (similar to LCA/RP). Eye signs are supersensitivity to bright light (photophobia) and rapid swinging or wobbling of the eye (nystagmus). Even worse is that severe heart problems (cardyomyopathy) are also seen in AS as well as possible liver and kidney disease. High weight gain is often seen in the first year of life.
D) Tests that are helpful in Diagnosing and Assessing LCA
1) Visual Acuity and Visual Field: Visual Acuity measures the ability of the eye to see objects at a certain distance directly ahead. It is usually measured by the well known letter chart hanging on the wall in the doctor’s office. Visual Field tests measure the degree of peripheral vision in a particular eye. The test can be as unsophisticated as being able to see the doctor’s hand motion in the periphery of the field of vision or through computerized “perimetry” using high tech machines.
2) Electroretinography (ERG): The normal retina produces electrical signals that can be easily detected outside the eye by specialized equipment. In many diseases such as LCA, both the magnitude and the pattern of this electrical signal are altered. In ERG, a contact lens electrode is placed on the front of the eye and the patient is presented with standardized light flashes. This can be done under standard room lighting or after the patient has been “dark adapted” by keeping them in a darkened room for a period of time. Frequency of the flash as well as brightness and color can be changed to glean additional information. Usually as a retinal degeneration progresses, the ERG readings get progressively smaller until they may finally be “extinguished”.
3) Visual Evoked Potential (VEP): To see, we must have proper brain function as well as retinal function since much processing and integration of the visual signal takes place in the brain, not the retina. In a VEP test, the patient views different patterns presented to them on a screen. Electrical activity from the brain is then measured from electrodes attached to the head. This is an important test as it is a non-invasive measure of the function of the entire visual system – retina to brain.
4) Ocular Coherence Tomography (OCT): OCT is a relatively new, non-invasive method that allows the Ophthalmologist to view cross-sectional images of the retina. Essentially, this measures the thickness of the retina and assesses its integrity. The retina is a highly structured tissue with discrete layers much like a bakery layer cake. In OCT, light waves of a particular type are directed into the eye. This light is then detected by special instruments as it is bounced back out of the eye (i.e., reflected) from the different retinal layers. In this way, the ophthalmologist can get an accurate topological or cross-sectional view of the patient’s retina. In the retinas of many LCA patients, the photoreceptor cells die, causing the photoreceptor layer to “thin”. This can be easily assessed by OCT and becomes a measure of the number of viable photoreceptor cells. This assessment is particularly important in determining possible therapeutic treatment since lack of photoreceptors would preclude certain future treatments such as Gene Therapy.
A Bionic Eye
Researchers are racing to perfect an artificial retina that could restore limited sight to the blind.
ELLEN DURCKEL
PRINT EDITION CONVERGENCE | May 29, 2008
No one would ever confuse William Boyd with Steve Austin, the iconic—and bionic—hero of the ‘70s TV series The Six Million Dollar Man. Austin was a top astronaut for NASA whose crash-related injuries led to substantial reengineering of various body parts by way of high-tech implants. Boyd spent his career at the considerably less glamorous Nabisco Bakery in Houston, Texas, mixing the dough that yields Ritz Crackers. In order to regain his fading vision, however, Boyd now hopes to become something of a bionic man himself, or at least a man with a bionic eye. In 1979, the then 36-year-old father of four began to notice that his eyesight, including his peripheral vision, was changing. He would transfer large tubs of dough onto floor jacks for a trip to the elevator, and then bump into things. It got so bad that his supervisor asked if he’d been drinking. Boyd eventually went to the doctor, and the diagnosis was devastating: retinitis pigmentosa, or RP, a genetic condition that causes degeneration of the natural photoreceptors—the rods and cones—that line the retina in the back of the eye. The next year, Boyd was forced to retire, his vision so compromised that, to get around, he was forced to rely on a cane and on the help of his daughters. Now, nearly three decades later, Boyd finally has some hope for improvement. And it rests with his ophthalmologist, Dr. Charles Garcia, and his entrepreneurial efforts to develop an artificial retina which could be implanted in patients. The basic science underlying the device was developed thanks to research sponsored by the ultimate source of Steve Austin’s fictional transformation—the U.S. space program. “Eventually I’ll be completely blind,” says Boyd, now 65. “What do I have to lose?” To develop the device, Garcia, who is on the faculty at the University of Texas Medical School at Houston, set up a company called Virtual Vision in 2003. Privately owned and angel funded, Virtual Vision is one of several companies that have spun out of research at the University of Houston’s Center for Advanced Materials, one of 11 previously NASA-sponsored Research “Our hope is that the thinfilm ceramic sensors will serve as substitutes for the damaged rods and cones in the eye stimulating the brain to see in much the same way the cochlear implant stimulates the brain to hear.”
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Partnership Centers. The artificial retina, Virtual Vision’s only product in development, is a thin film consisting of 100,000 ceramic detectors, each of which is five microns in diameter—the same size as the natural photoreceptor rods and cones in the human eye.
These detectors essentially perform the work that the diseased eye’s faulty rods and cones are no longer capable of doing. When working properly, the natural structures convert light to electrical impulses that then travel along 1.2 million neurons in the optic nerve to the brain, where they are processed into coherent images. The natural rods, cylindrical in shape, can detect a single photon, which means they are 100 times more sensitive to light than the cones.
Accordingly, the rods allow for vision in low light, but they respond more slowly than cones. Cones require more light, but they provide finer detail and a faster response time that allows clear perception of rapidly changing images. Cones are also sensitive to color.
“Our hope is that the thin-film ceramic sensors will serve as substitutes for the damaged rods and cones in the eye stimulating the brain to see in much the same way the cochlear implant stimulates the brain to hear,” says Virtual Vision Vice President Alex Ignatiev, who is also the director of the Center for Advanced Materials at the University of Houston.
Retinitis pigmentosa is one of the two leading causes of vision loss in the United States, Western Europe, and Japan, along with another impairment of the rods and cones: age-related macular degeneration. RP can lead to tunnel vision, impaired night vision, and often total blindness. Any effective treatment, bionic or otherwise, would be a major development.
“These are diseases where the sensors in the eye, the rods and cones, have deteriorated but the rest of the wiring is still in place,” says Ignatiev. The artificial retina is designed to electrically stimulate the other structures—the bipolar cells, Mueller Cells, and the retinal neurons that play a key role in communicating with the optic nerve to produce sight—that remain essentially intact.
The artificial detectors are so small that they must be attached to a polymer film a few millimeters in size, which is then surgically implanted into the eye. Two weeks later, the polymer film dissolves, leaving the array behind. “We have been using nanotechnology since its inception,” says Ignatiev, referring to materials science focused on the manipulation and control of matter at a scale of 1 to 100 nanometers, otherwise known as 1 billionth of a meter. “We are currently making the ceramic detectors about 10 times larger, at about 40 micrometers, but that’s because you can easily see them with a microscope.” The discovery of one of the key components of the artificial retina was something of an accident. Ignatiev had been working on a night vision project for NASA when he came upon the ceramic material—a member of a unique class of materials called uncooled infrared detectors—he now uses in the artificial retina.
“We found that this ceramic material was not only sensitive to heat but also to light,” he says. The idea came to him that it might be useful to people with vision problems. Being able to manipulate it at a submicroscopic level was essential; fortunately, it retained its properties at the nanoscale.
E. Brady Trexler, an Assistant Professor in the Department of Opthamology and Neuroscience at Mount Sinai School of Medicine, says Ignatiev’s ability to create an array of nanoscale photodetectors mimicking the array of cone photoreceptors in size and function places the technology on firm footing as a viable therapy for restoring vision. “The beauty of the design lies in its simplicity,” he says. “In retinal degeneration, photoreceptors are the first to go, and more complex neurons remain, at least for a while. Our hope is that ceramic photodetectors will stimulate the surviving neurons to induce vision.”
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Building an artificial retina is an extremely painstaking process. The films that hold the artificial retina detectors are grown atom by atom and layer by layer on a background substrate—a technique called molecular beam epitaxy, which has been described as a super-gentle form of atom spray painting that enables layers as thin as one atom to be placed on top of one another.
“Well ordered, epitaxally grown films have the best optical properties,” says Ignatiev. Although the technology’s development has roots in space exploration, it also derives from expertise developed in the semiconductor industry. Virtual Vision uses that expertise to make the arrays like chips in a computer factory. The nanodetectors are stacked in a hexagonal structure in an array mimicking the arrangement of the human rods and cones they are designed to replace. But molecular beam epitaxy was in fact perfected during NASA experiments conducted in 1996 on the Wake Shield Facility, a 12-foot-diameter, disk-shaped platform designed by the Center for Advanced Materials to study epitaxal thin-film growth in the ultra vacuum of space. It was launched from the space shuttle Columbia during the STS-80 mission.
“We grew thin oxide films using atomic oxygen in low earth orbit as a natural oxidizing agent,” says Ignatiev. “Those experiments helped us develop the oxide ceramic detectors we’re now using.”
Ignatiev’s artificial retina has overcome many of the challenges faced by earlier attempts. The natural layout of the individual detectors solves another problem that plagued earlier siliconbased research: blockage of nutrient flow to the eye. “All of the nutrients feeding the eye flow from the back to the front,” says Ignatiev. “If you implant a silicon detector into the eye, nutrients can’t flow through it, and the neural cells of the eye will atrophy.”
Scientists at John Hopkins University, MIT, and elsewhere have tried to build artificial rods and cones before, he notes. Most of these earlier efforts involved either electrode implantation into the interior of the eye or silicon-based solar cell implantation into the eye. Silicon, like any foreign substance, can be toxic to the human body and reacts unfavorably with fluids in the eye—problems the ceramic detectors do not share. But even space-age research is still subject to the whims of Mother Nature. Garcia, the ophthalmologist treating Boyd, was humbly reminded of such limits during his early animal experiments. Initially, he implanted ceramic detectors in 10 rabbits at the University of Texas Medical School to test for bio-compatibility. The rabbits, however, drowned along with thousands of other research animals when tropical storm Allison hit in 2001, dropping over 35 inches of rainfall on Houston in two days. Throughout the Texas Medical Center, where the medical school is located, thousands of laboratory animals were lost along with decades of research and for many scientists, their life’s work.
Despite the initial setback, Garcia went on to implant 48 rabbits between 2002 and 2004. The results in the animals were encouraging: There were no signs of toxicity or tissue reaction for up to 24 months. The data was not published but was presented twice in 2003 to the Association for Research in Vision and Ophthalmology.
Virtual Vision is now ready to implant the nano device in retinally blind patients, an experiment Garcia expects to begin within the next few years. He plans to conduct this work in Mexico, where the cost of clinical trials is lower than in the United States, and where he has done many other research projects.
Still, others urge caution. “There is some fundamental work that needs to be done before they are ready for human trials,” says William Foster, M.D., Ph.D., a research professor of physics at the University of Houston and Clinical Associate Professor of Ophthalmology at Weill-Cornell
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Medical College who earlier worked with Ignatiev on the project. Foster says that this work, which affects the neurons on the surface of the retina, needs the involvement of neuroscientists.
The ceramic material contains lead, he says, and may not be stable during long-term implantation in the body. For this reason, encapsulation of the device may be important to avoid the release of the lead into the surrounding tissue.
Toxicity due to low levels of lead can be subtle, and may not have shown up in their studies, he adds. In addition, the function of the device may be impaired by the formation of scar tissue around it. The next step, Foster says, should be further testing in primates.
But Ignatiev says his team has already complied with federal regulations. “The rabbits were implanted with the artificial retinas and wore them for 24 months without any toxic effects or any other negative response,” he says. “This is the standard requirement of the Food and Drug Administration.”
After eight years of work on the artificial retina and two patents for the technology, Ignatiev and Garcia would like to proceed. “Our detectors are doing from a physics perspective what they should do,” says Ignatiev. “Is it good enough so that when in the eye they will send a signal to the brain? We don’t know. That’s what we need to find out.” Ignatiev adds that the brain is a powerful tool and already has shown it can relearn how to hear with the cochlear implant. “We think it can relearn how to see with the retinal implant,” he says.
But as Garcia admits, “This is a Model T Ford. We hope a person could see the edge of shapes and perhaps get some limited improvement in their field of vision. It will certainly not produce the kind of vision needed for reading.”
In the meantime, patients like William Boyd remain hopeful. “It would be fine by me to be one of the first patients to be implanted with the artificial retina,” he says. “Each month that passes, my vision only gets worse.”
Ellen Durckel is a freelance medical journalist and television producer for ABC News based in Houston.
The Journal of Life Sciences | Print version
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U.S. Court: Dollars Discriminate Against Blind
Federal appeals court ruling could force U.S. to redesign paper money
The Associated Press
updated 11:49 a.m. ET, Tues., May. 20, 2008
WASHINGTON - The U.S. discriminates against blind people by printing paper money that makes it impossible for them to distinguish among the bills’ varying values, a federal appeals court ruled Tuesday.
The ruling upholds a decision by a lower court in 2006. It could force the Treasury Department to redesign its money. Suggested changes have ranged from making bills different sizes to printing them with raised markings.
The American Council for the Blind sued for such changes but the Treasury Department has been fighting the case for about six years.
“I don’t think we should have to rely on people to tell us what our money is,” said Mitch Pomerantz, the council’s president.
The U.S. acknowledges the design hinders blind people but it argued that blind people have adapted. Some relied on store clerks to help them, some used credit cards and others folded certain corners to help distinguish between bills. The court ruled 2-1 that such adaptations were insufficient. The government might as well argue that, since handicapped people can crawl on all fours or ask for help from strangers, there’s no need to make buildings wheelchair accessible, the court said.
Courts can’t decide how to design the currency, since that’s up to the Treasury Department. But the ruling forces the department to address what the court called a discriminatory problem.
Pomerantz says it could take years to change the look of money and until then, he expects that similar-looking money will continue to get printed and spent. But since blindness becomes more common with age, people in the 30s and 40s should know that, when they get older, “they will be able to identify their $1 bills from their fives, tens and twenties,” he said.
Officials at the Treasury Department and the department’s Bureau of Engraving and Printing, which prints the nation’s currency, had no immediate comment on the ruling. The government could appeal to the Supreme Court.
While the government has been fighting to overturn the lower court ruling, it has been taking some steps toward modifying U.S. currency for the visually impaired.
The most recent currency redesign of the $5 bill introduced in March features a giant “5” printed in purple on one side of the bill to help those with vision problems distinguish the bill.
The appeals court also ruled that the U.S. failed to explain why changing the money would be an undue burden. The Treasury Department has redesigned its currency several times in recent years, and adding features to aid the blind would come at a relatively small cost, the court said.
Other countries have added such features, the court said, and the U.S. never explained what made its situation so unique.
© 2008 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
URL: http://www.msnbc.msn.com/id/24725916/
Stephen M. Rose, Ph.D., Chief Research Officer
Foundation Fighting Blindness
11435 Cronhill Drive, Owings Mills, MD 21117-2220
phone (410) 568-0125 fax (410) 363-4692
srose@fightblindness.org
http://www.fightblindness.org/
Driving research to save and restore sight
