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Gene Therapy Improves Vision in Patients with Congenital Retinal Disease

Patients' Vision Improved from Detecting Hand Movements to Reading Lines on Eye Chart

PHILADELPHIA, April 27 /PRNewswire-USNewswire/ -- In a clinical trial at The Children's Hospital of Philadelphia, researchers from The University of Pennsylvania have used gene therapy to safely restore vision in three young adults with a rare form of congenital blindness. Although the patients have not achieved normal eyesight, the preliminary results set the stage for further studies of an innovative treatment for this and possibly other retinal diseases.

An international team led by The University of Pennsylvania, The Children's Hospital of Philadelphia, the Second University of Naples and the Telethon Institute of Genetics and Medicine (both in Italy), and several other American institutions reported their findings today in an online article in the New England Journal of Medicine.

"This is the first gene therapy trial for a nonlethal pediatric condition," said Albert M. Maguire, M.D., Associate Professor, Department of Ophthalmology, University of Pennsylvania School of Medicine and a physician at The Children's Hospital of Philadelphia. Maguire, together with his wife, Jean Bennett, M.D., Ph.D., Professor of Ophthalmology at Penn and Senior Investigator at the F.M. Kirby Center for Molecular Ophthalmology at Penn's Scheie Eye Institute, have been researching inherited retinal degenerations such as Leber congenital amaurosis (LCA), for 18 years. LCA is a group of inherited blinding diseases that damages light receptors in the retina. It usually begins stealing sight in early childhood and causes total blindness during a patient's twenties or thirties. Currently, there is no treatment for LCA.

"Patients' vision improved from detecting hand movements to reading lines on an eye chart," Maguire added. In 2001, Bennett and Maguire were part of a team which reported successfully reversing blindness using gene therapy on dogs affected by the same naturally occurring form of congenital blindness.

The current study is sponsored by the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, directed by Katherine A. High, M.D. High, a study leader and an Investigator of the Howard Hughes Medical Institute, has been a pioneer in translational and clinical studies of gene therapy for genetic disease, and in 2005 initiated a collaboration with Bennett and her group to translate their exciting animal findings into a clinical study.

The scientists used a vector, a genetically engineered adeno-associated virus, to carry a normal version of the gene, called RPE65, that is mutated in one form of LCA. Three patients, ages 19, 26 and 26, received the gene therapy via a surgical procedure performed by Maguire between October 2007 and January 2008 at The Children's Hospital of Philadelphia, where the gene vector was manufactured at the hospital's Center for Cellular and Molecular Therapeutics (CCMT).

Starting two weeks after the injections, all three patients reported improved vision in the injected eye. "Standard vision tests showed significantly improved vision in the patients," said Alberto Auricchio, M.D., a study leader from the Telethon Institute of Genetics and Medicine and University of Naples Federico II. The researchers also reported that each injected eye became approximately three times more sensitive to light, and each was improved compared to the uninjected, previously better functioning eye.

The LCA gene therapy vector showed no signs of causing inflammation in the retina or other toxic side effects. One of the three patients had an adverse event, a hole in the retina that did not affect eyesight and may have been surgery-related, rather than related to biological effects of the therapeutic gene or the vector used to carry it.

The patients enrolled in the study to date were identified at the Department of Ophthalmology at the Second University of Naples, an institution with long-standing experience in collecting and studying patients with inherited retinal diseases, under the supervision of Francesca Simonelli, M.D.

Testing continued over a period of six months following the gene therapy vector administration. One patient was better able to navigate an obstacle course compared to before the injection. The patients also had less nystagmus, an involuntary movement of the eyes that is common in LCA. In the patient who experienced better vision even in the uninjected eye, the researchers suggest that the reduced nystagmus benefited both eyes.

"The current clinical trial will continue with more patients and with ongoing follow-up to monitor results," said Bennett. "We expect improvements to be more pronounced if treatment occurs in childhood, before the disease progresses."

"This result is important for the entire field of gene therapy," notes High, a past president of the American Society of Gene Therapy. "Gene transfer has been in clinical trials for over 15 years now, and although it has an excellent safety record, examples of therapeutic effect are still relatively few. The results in this study provide objective evidence of improvement in the ability to perceive light, and thus lay the groundwork for future studies in this and other retinal disorders," said High.

The pace of moving from pre-clinical discoveries into clinical trials has typically been slow in the field of gene therapy due to the breadth of expertise required, ranging from in-depth knowledge of the disorder to detailed understanding of vector design, manufacture, and pre-clinical evaluation. The complexities of regulatory oversight at both the federal and local levels also present challenges. Through the Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia has developed concentrated expertise and substantial resources to facilitate the "bench to bedside" translation of gene therapy.

The scientists at the Clinical Vector Core at CCMT have over 30 years experience in the biopharmaceutical industry and in 2007 were awarded a National Institutes of Health contract for clinical grade vector production for trials throughout the United States, attesting to the quality of their vector manufacture. The CCMT's dedicated regulatory affairs support has specialized expertise in clinical gene therapy and coordinates trial approvals from multiple scientific and ethic review committees, manages the study activities at all clinical sites, and ensures compliance with international quality standards for conducting, monitoring, and reporting clinical trials.

The clinical trial was sponsored and primarily funded by the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. Research support was received from The Department of Ophthalmology at the University of Pennsylvania, the F.M. Kirby Foundation, the Foundation Fighting Blindness, Research to Prevent Blindness, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, the Rosanne H. Silbermann Foundation, the Italian Telethon Foundation, the Associazione Italiana Amaurosi Congenita di Leber, the National Center for Research Resources, the Howard Hughes Medical Institute, the National Eye Institute of the National Institutes of Health, private philanthropy, and an anonymous donor who is committed to advancing pediatric medicine through maximizing the potential of gene therapy.

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit

About the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia: The Center for Cellular and Molecular Therapeutics was established in 2005, with a mission of fostering a multidisciplinary approach to the development of new cell and gene therapies for the treatment of serious and debilitating childhood disorders. The Center conducts cutting edge research in gene transfer, gene regulation, gene discovery, stem cell biology, experimental models of disease, and correction of genetic disease. Consistent with Children's Hospital's research mission to transform scientific insights into improved medical therapies, the Center has the capacity to support rapid translation of promising results from the laboratory to the clinic, through facilities for manufacturing clinical-grade gene therapy vectors for clinical studies, and through specialized regulatory support for the design and implementation of clinical trials of complex, novel classes of therapeutics.

About The University of Pennsylvania School of Medicine's Department of Ophthalmology and The Scheie Eye Institute: Scheie Eye Institute is the Department of Ophthalmology at the University of Pennsylvania. Its ten clinical divisions include the Division of Pediatric Ophthalmology which is housed at The Children's Hospital of Philadelphia. The Department of Ophthalmology ( is also home to the F.M. Kirby Center for Molecular Ophthalmology, founded in 1994 with a generous gift from the F.M. Kirby Foundation, which has provided continuous support for the ongoing research for the past 14 years. The F.M. Kirby Center was the first molecular biology center devoted to developing gene therapy for hereditary causes of vision loss. The Center serves as home to the laboratories of seven investigators who conduct research on the cellular and molecular biology of eye disease and visual function. Current studies in the F.M. Kirby Center include evaluations of the molecular genetics and pathogenetic mechanisms involved in optic nerve disease and inherited retinal and macular degenerations, cell biology studies of photoreceptor sensory cilia, delineation of mechanisms underlying the light responses of rods and cones, gene discovery of complex and monogenic disorders, development of methods with which to non-invasively monitor retinal and visual function in animal models and humans, and design of novel methods with which to image retinal cells. (

The Department of Ophthalmology (Scheie Eye Institute) at Penn is a world leader in patient care and eye and vision research. In 2006, the most recent year for which published data are available, Scheie Eye Institute was the #1 recipient of eye research funds from the National Eye Institute, National Institutes of Health among all departments of ophthalmology in the United States. Currently the National Eye Institute is funding a 46-site randomized clinical trial to evaluate treatment strategies for age-related macular degeneration coordinated by faculty at Scheie Eye Institute at Penn.

About The Telethon Institute of Genetics and Medicine (TIGEM): TIGEM is a local and international reference for research on human genetic diseases. It was created in 1994 by the Telethon Foundation, one of Italy's major non-profit organizations, to promote the advancement of research aimed at the diagnosis, cure and prevention of human genetic diseases. TIGEM's mission is to understand the mechanisms of genetic diseases and to develop preventive and therapeutic strategies. Since its establishment, the Institute has grown considerably. It now consists of a large fully refurbished site, and comprises 13 independent research groups with over 170 members including graduate students, postdoctorate fellows, technicians and administration. The scope of the science currently covered at TIGEM spans three disease research area: developmental disorders, inborn errors of metabolism and inherited eye diseases. Research approaches include cell biology, functional genomics, systems biology and gene therapy. TIGEM offers training programs in medical and human genetics, in cooperation with local and international universities such as the British Open University. Research activity at TIGEM is supported by core facilities dedicated to providing state-of-the-art technology as well as housekeeping assistance.

About the Howard Hughes Medical Institute (HHMI): HHMI, a non-profit medical research organization that ranks as one of the nation's largest philanthropies, plays a powerful role in advancing biomedical research and science education in the U.S. In the past two decades HHMI has made investments of more than $8.3 billion for the support, training, and education of the nation's most creative and promising scientists. HHMI's flagship program in biomedical research rests on the conviction that scientists of exceptional talent, commitment, and imagination will make fundamental biological discoveries for the betterment of human health if they receive the resources, time, and freedom to pursue challenging questions. The 298 investigators of HHMI, selected through rigorous national competitions, include 12 Nobel Prize Winners and 122 members of the National Academy of Sciences. Founded in 1953 by Howard R. Hughes, the aviator and industrialist, HHMI is headquartered in Chevy Chase, Maryland, and employs more than 2,600 individuals across the U.S.

SOURCE The Children's Hospital of Philadelphia; University ofPennsylvania
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