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 http://www.chop.edu.
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 (http://www.uphs.upenn.edu/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.
(http://www.uphs.upenn.edu/news)
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 of
Pennsylvania
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Related links:
http://www.chop.edu
http://www.uphs.upenn.edu/
CONTACT:
Joey Marie McCool of The Children's Hospital
of Philadelphia, +1-215-662-2560, +1-267-258-6735 (cell),
McCool@email.chop.edu; or Karen Kreeger University of
Pennsylvania School of Medicine, +1-267-426-6070, +1-215-459-0544
(cell), Karen.kreeger@uphs.upenn.edu
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