Gene therapy improves vision in patients with congenital retinal
disease
Patients' vision improved from detecting hand movements to reading
lines on eye chart
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.
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.
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.
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-
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
Public release date: 27-Apr-2008
Contact: Joey Marie McCool
McCool@email.
267-426-6070
215-258-6735 (cell)
The Children's Hospital of Philadelphia
Karen Kreeger
Karen.kreeger@
215-662-2560
215-459-0544 (cell)
University of Pennsylvania School of Medicine
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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