Improving the longevity of functionally integrated stem cells in regenerative vision therapy

Buck scientists restore long-term vision in blind mice, making a case for addressing the immune system’s role in rejecting transplanted cells January 12, 2017/Novato, California:  Stem cell therapies hold great promise for restoring function in a variety of degenerative conditions, but one of the logistical hurdles is how to ensure the cells survive in the body long enough to work. Researchers from the Buck Institute report one of the first demonstrations of long-term vision restoration in blind mice by transplanting photoreceptors derived from human stem cells and blocking the immune response that causes transplanted cells to be rejected by the recipient. Publishing in the Cell Stem Cell, this work highlights immune system rejection as one of the key issues that needs to be addressed to improve efficiency of stem cell regeneration therapies. The findings support a path to improving clinical applications, specifically for restoring vision in humans by allowing photoreceptors derived from human stem cells to integrate and thrive in the eye. “This turned into a nice story of long-term restoration of vision in completely blind mice,” said Buck faculty and senior author Deepak Lamba, PhD, MBBS. “We show that these mice can now perceive light as far out as 9-months following injection of these cells.” Photoreceptors are specialized neurons in the retina that convert light into signals that the brain interprets as sight. Loss of these cells is a common endpoint in degenerative eye diseases. Human embryonic stem cells can provide a potential source for photoreceptor replacement, but despite Lamba’s prior work showing that photoreceptors derived from stem cells could function in mice, researchers   hadn’t been able to show long-term sustained vision restoration. A major controversy in field, said Lamba, was whether the transplanted [...]

Novel gene-editing method improves vision in blind rats

December 6, 2016 At a Glance Scientists developed a targeted gene-replacement technique that can modify genes in both dividing and non-dividing cells in living animals. The method enabled replacement of a faulty gene in neurons and partially restored vision in blind rats. The technique thus holds promise as a potential tool for gene therapy. The green-colored cells are neurons in a mouse brain that were successfully modified using the new gene-editing technique. Izpisua Belmonte Lab, Salk Institute Gene-editing techniques like CRISPR/Cas9 can successfully replace faulty genes, and scientists have been exploring their therapeutic potential. But insertion of new genes has generally been limited to dividing cells, like those in the skin and gut, because the techniques depend on processes that are only active during cell division. Most of the body’s cells, however, are non-dividing, including those in the eye, brain, and heart. To address this limitation, a group of researchers led by Dr. Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies in San Diego set out to develop a more versatile approach. Their goal was to develop a technique that could insert new genes even into cells that weren’t dividing. The research was funded in part by NIH’s National Heart, Lung, and Blood Institute (NHLBI). Results were published in Nature on December 1, 2016. The researchers focused on a DNA-repair mechanism called NHEJ (non-homologous end-joining). NHEJ repairs DNA breaks by rejoining broken DNA ends. It’s active in both dividing and non-dividing cells. This makes it a useful partner to the CRISPR/Cas9 gene-editing tool, which can snip out DNA pieces at precise locations. The scientists tailored the NHEJ machinery for use along with CRISPR/Cas9. They named the new approach HITI (homology-independent targeted integration). [...]

New gene-editing technology partially restores vision in blind animals

November 16, 2016Salk researchers have discovered, for the first time, how to place DNA in specific locations in non-dividing cells LA JOLLA—Salk Institute researchers have discovered a holy grail of gene editing—the ability to, for the first time, insert DNA at a target location into the non-dividing cells that make up the majority of adult organs and tissues. The technique, which the team showed was able to partially restore visual responses in blind rodents, will open new avenues for basic research and a variety of treatments, such as for retinal, heart and neurological diseases. “We are very excited by the technology we discovered because it’s something that could not be done before,” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and senior author of the paper published on November 16, 2016 in Nature. “For the first time, we can enter into cells that do not divide and modify the DNA at will. The possible applications of this discovery are vast.” Until now, techniques that modify DNA—such as the CRISPR-Cas9 system—have been most effective in dividing cells, such as those in skin or the gut, using the cells’ normal copying mechanisms. The new Salk technology is ten times more efficient than other methods at incorporating new DNA into cultures of dividing cells, making it a promising tool for both research and medicine. But, more importantly, the Salk technique represents the first time scientists have managed to insert a new gene into a precise DNA location in adult cells that no longer divide, such as those of the eye, brain, pancreas or heart, offering new possibilities for therapeutic applications in these cells. To achieve this, the Salk researchers targeted a DNA-repair cellular pathway [...]

New, regenerative medicine approach developed to remove congenital cataracts in infants

Published on March 10, 2016 at 1:59 AM Researchers at University of California, San Diego School of Medicine and Shiley Eye Institute, with colleagues in China, have developed a new, regenerative medicine approach to remove congenital cataracts in infants, permitting remaining stem cells to regrow functional lenses. The treatment, which has been tested in animals and in a small, human clinical trial, produced much fewer surgical complications than the current standard-of-care and resulted in regenerated lenses with superior visual function in all 12 of the pediatric cataract patients who received the new surgery. The findings are published in the March 9 online issue of Nature. Congenital cataracts - lens clouding that occurs at birth or shortly thereafter - is a significant cause of blindness in children. The clouded lens obstructs the passage of light to the retina and visual information to the brain, resulting in significant visual impairment. Current treatment is limited by the age of the patient and related complications. Most pediatric patients require corrective eyewear after cataract surgery. "An ultimate goal of stem cell research is to turn on the regenerative potential of one's own stem cells for tissue and organ repair and disease therapy," said Kang Zhang, MD, PhD, chief of Ophthalmic Genetics, founding director of the Institute for Genomic Medicine and co-director of Biomaterials and Tissue Engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine. In the new research, Zhang and colleagues relied upon the regenerative potential of endogenous stem cells. Unlike other stem cell approaches that involve creating stem cells in the lab and introducing them back into the patient, with potential hurdles like pathogen transmission and immune rejection, endogenous stem cells are [...]

‘Miracle’ cells could cure blindness

By Kieron Monks, for CNN Updated 10:28 AM ET, Tue March 8, 2016 (CNN) It's the most common cause of blindness in the Western world and there is no cure. At least not yet. Age-related Macular Degeneration (AMD) affects around 15 million people in the U.S. alone, and globally up to 30 million. For most victims, vitamins and pain relief are the best treatment available. But Professor Pete Coffey of University College London is pioneering a new therapy that could stop the disease in its tracks, and restore vision to the blind, through the London Project to Cure Blindness. Discovery could save the sight of 30 million people AMD kills the eye's Retinal Pigment Epithelium (RPE), a layer of cells that support and nourish the eye's vision center, the macula, which then also gradually dies. Victims experience a black spot in their vision that grows outward, while they lose the ability to read and recognize familiar faces. Coffey has spent the past eight years creating and refining his treatment to restore vision and on August 11, 2015, the first patient received it. The landmark operation The patient was a 60-year-old woman suffering with a severe form of AMD. Blood vessels at the back of her eyes had burst, flooding the retina and rapidly destroying her vision. Surgeons at Moorfields Eye Hospital in London implanted a thin layer of cells behind the retina of each eye on a polyester patch just three millimeters wide. They used stem cells due to their ability to become many other cell types in the body. In this case, they had been cultivated as RPE cells to replace the patient's diminished stock. We had the cells in the dish and they [...]

$11.9 million from NIH funds glaucoma study

Researchers to evaluate effectiveness of earlier efforts to prevent, delay blinding eye disease by Jim Dryden•February 26, 2016 ROBERT BOSTON PHOTO Michael A. Kass, MD, will lead a nationwide study to determine whether efforts to prevent or delay the onset of glaucoma have been effective over the course of two decades. Researchers at Washington University School of Medicine in St. Louis have received four grants totaling $11.9 million from the National Eye Institute at the National Institutes of Health (NIH) to lead a nationwide study to determine whether efforts to prevent or delay the onset of glaucoma have been effective over the course of two decades. The new study is a follow-up to research led by the same Washington University scientists in the 1990s. That research, the Ocular Hypertension Treatment Study, was conducted at 22 clinical sites in the United States and followed 1,636 subjects ages 40-80. Now, 20 years later, the same researchers are following up with the same subjects to see how their original conclusions have held up. “We are going back to look at the same group of patients,” said Michael A. Kass, MD, lead investigator of the original study. “This is a landmark study because there just aren’t many 20-year studies conducted in vision research. We will conduct eye examinations to learn how many have developed glaucoma and, if so, how severe it is.” All of the patients in the original study had elevated pressure in the eye, called ocular hypertension, but during the first phase of the study, only half were treated with pressure-lowering eye drops. The researchers eventually found that patients at the highest risk for glaucoma needed to be treated — such as those who had elevated eye pressure and other symptoms including [...]

CRISPR Used to Repair Blindness-causing Genetic Defect in Patient-derived Stem Cells

A potential precision medicine approach for treating vision loss January 27, 2016 Columbia University Medical Center (CUMC) and University of Iowa scientists have used a new gene-editing technology called CRISPR to repair a genetic mutation responsible for retinitis pigmentosa (RP), an inherited condition that causes the retina to degrade and leads to blindness in at least 1.5 million cases worldwide. The study was published in Scientific Reports, and marks the first time researchers have replaced a defective gene associated with a sensory disease in stem cells that were derived from a patient’s tissue. “Our vision is to develop a personalized approach to treating eye disease,” says Stephen Tsang, MD, PhD, the László Z. Bitó Associate Professor of Ophthalmology and associate professor of Pathology & Cell Biology at CUMC, ophthalmologist at NewYork-Presbyterian/Columbia, and one of the study’s senior authors. “We still have some way to go, but we believe that the first therapeutic use of CRISPR will be to treat an eye disease. Here we have demonstrated that the initial steps are feasible.” In the study, the researchers created stem cells from a sample of skin that was taken from a patient with retinitis pigmentosa. As the patient-derived stem cells still harbored the disease-causing mutation, the teams used CRISPR to repair the defective gene. The stem cells can potentially be transformed into healthy retinal cells and transplanted back into the same patient to treat vision loss. “The X-linked form of retinitis pigmentosa is an ideal candidate for a precision medicine approach because a common mutation accounts for 90% cases,” Tsang explains. Using CRISPR —which is easily adaptable to diverse sequences of DNA, and allows for fast and accurate editing —scientists can take a patient’s own cells [...]

National honor for helping “the blind see”

JANUARY 7, 2016 / KEVIN MCCORMACK, CIRM blog Those of us fortunate to have good health take so many things for granted, not the least of which is our ability to see. But, according to the World Health Organization, there are 39 million people worldwide who are blind, and another 246 million who are visually impaired. Any therapy, any device, that can help change that is truly worthy of celebration. Dr. Mark Humayun: Photo courtesy USC That’s why we are celebrating the news that Professor Mark Humayun has been awarded the National Medal of Technology and Innovation, the nation’s top technology honor, by President Obama. Humayun, a researcher at USC’s Keck School of Medicine and a CIRM grantee, is being honored for his work in developing an artificial retina, one that enables people with a relatively rare kind of blindness to see again. But we are also celebrating the potential of his work that we are funding that could help restore sight to millions of people suffering from the leading cause of blindness among the elderly. But we’ll get back to that in a minute. First, let’s talk about the invention that has earned him this prestigious award. It’s called the Argus II and it can help people with retinitis pigmentosa, an inherited degenerative disease that slowly destroys a person’s vision. It affects around 100,000 Americans. The Argus II uses a camera mounted on glasses that send signals to an electronic receiver that has been implanted inside the eye. The receiver then relays those signals through the optic nerve to the brain where they are interpreted as a visual image. In a story posted on the USC website, USC President C. L. Max Nikias praised [...]

Some Stem Cells Are Rejected, Some Aren’t, Says iPSC Work

Wed, 10/21/2015 - 9:38am Cynthia Fox, Science Writer Embryonic stem (ES) cell-like stem cells made from adult cells—and morphed into eye cells—are not rejected by the immune system, according to “humanized mouse” data in Cell Stem Cell. Coming alongside news that the first UK macular degeneration patient received eye cells made from normal ES cells, the study spells hope that many patients’ adult cells may soon be turned into potent ES cell-like cells (induced pluripotent stem cells (iPSCs))—and then new eye cells—to fight blindness. The Cell Stem Cell paper also offered a different kind of eye-opener however: while eye cells (called retinal pigment epithelium (RPE)) cells from iPSCs are accepted by the immune system, other cells from the same iPSCs may be rejected: smooth muscle cells (SMCs). “I found this paper striking,” Paul Knoepfler, Ph.D., University of California, Davis, iPSC expert, told Bioscience Technology. Knoepfler was uninvolved with the study. “There was a presumption that we could make cells from iPSCs and give them back to the patient and not worry about it. That this may not always be true should be on our radar screens, especially given the momentum out there to do clinical studies with iPSCs.” “This paper addresses key questions in the field of regenerative medicine; mainly, understanding the immunogenicity of pluripotent stem cell derivatives,” Stanford Cardiovascular Institute Director Joseph Wu, M.D., Ph.D., told Bioscience Technology. Wu was also uninvolved. “Future studies will need to focus on further improvement of the humanized mouse model, which can be used to help us design clinically applicable immunosuppression regimens.” Paul Fairchild, D.Phil., co-director of the University of Oxford Stem Cell Institute, also researches iPSC immunogenicity. "This is an elegant piece of work, which appears to [...]

A new treatment for macular degeneration

A patient receives the first human eye cell transplant developed by a UCSB neuroscientist who founded the London Project to Cure Blindness By Julie Cohen Monday, September 28, 2015 - Santa Barbara, CA A clinical trial using stem cell-derived ocular cells for the treatment of wet age-related macular degeneration (AMD) has been initiated in England. This was a major milestone for the London Project to Cure Blindness, which aims to cure vision loss in people with wet AMD. The organization was founded 10 years ago by UC Santa Barbara’s Peter Coffey, a professor at the campus’s Neuroscience Research Institute. The surgery was performed on a patient last month and no complications have arisen to date. The team hopes to determine the patient’s outcome in terms of initial visual recovery by early December. “Cellular therapy has tremendous potential for treating all types of age-related macular degeneration,” said Coffey’s colleague Dennis Clegg, the Wilcox Family Chair in BioMedicine in UCSB’s Department of Molecular, Cellular, and Developmental Biology. “Regenerative medicine using stem cells will likely become a major weapon to fight many diseases.” Clegg is also co-director of the California Project to Cure Blindness, a collaborative effort aimed at developing a stem-cell-based therapy for AMD. The project is funded by the California Institute for Regenerative Medicine (CIRM), the state’s stem cell agency, which funds Coffey’s research at UCSB. Macular degeneration accounts for almost 50 percent of all visual impairment in the developed world and usually affects people over 50 years of age. In people with AMD, the central (reading) vision is affected while the surrounding vision remains normal. AMD takes two forms: wet and dry. Wet AMD is generally caused by abnormal blood vessels that leak fluid or blood into [...]