An international team of scientists and clinicians from the United States
and Saudi
Arabia are working to develop gene therapy for treating a rare, hereditary
retinal
disease. The therapy has been shown to restore lost vision in animal models
of retinitis
pigmentosa (RP). Their work is being funded in part by a $1.5 million grant
from
the Prince Salman Center for Disability Research in Saudi Arabia, where the
recessive
gene mutation that leads to the eye disease RP has been found in children
from several
families.
The study is being led by Kang Zhang, MD, PhD, professor of ophthalmology at
the
University of California, San Diego School's Shiley Eye Center and director
of the
UCSD Institute for Genomic Medicine, and Fowzan Alkuraya, MD, senior
clinical scientist
and head of developmental genetics unit at King Faisal Specialist Hospital
and Research
Center, Saudi Arabia.
RP is a type of hereditary retinal dystrophy, a group of inherited disorders
in which
abnormalities of the photoreceptor rods and cones lead to progressive visual
loss.
Rods and cones are specialized light-sensitive nerve cells that line the
retina.
They collect light and then send nerve signals that the brain interprets as
vision.
Rods facilitate black and white vision and are used mainly at night. During
the day,
humans depend on cones for color vision.
In people with the genetic mutations that cause RP, rods and cone cells die.
Affected
individuals first experience defective dark adaptation or "night blindness,"
followed
by reduction of the peripheral visual field known as tunnel vision,
sometimes followed
by loss of central vision late in the course of the disease. RP affects one
in 3,000
to 4,000 people in the United States.
The planned clinical approach of this research trial involves a receptor
protein
called MERTK that is expressed in the retinal pigment epithelium, the
pigmented cell
layer just outside the retina that closely interacts with photoreceptors in
the maintenance
of visual function. Patients with loss of MERTK function have a defect in
phagocytosis
?" a mechanism used to remove pathogens and cell debris. As a result of this
defect,
debris accumulates between the photoreceptors and retinal pigment
epithelium, resulting
in death of photoreceptors and loss of vision.
The researchers plan to deliver the MERTK gene in a viral vector - a carrier
commonly
used to deliver genetic material to treat these cells in order to restore
function
of photoreceptors. Using a rodent model of RP with a similar MERTK mutation,
the
researchers have demonstrated in proof-of-concept studies that viral vector
delivery
of MERTK corrects the mutant gene and restores vision.
The eye is an ideal place for gene therapy because it's an
"immune-privileged site,"
meaning that the eye is able to tolerate the introduction of foreign cells
with a
minimal, if any, inflammatory immune response, according to Zhang.
The research team's next step is to show that such gene therapy is safe in
further
animal studies, to be conducted in China, along with additional rat studies
that
will be conducted at UC San Diego and at the University of Florida.
Once safety for the procedure has been shown, the team hopes to proceed to a
human
clinical trial in seven patients identified in Saudi Arabia, perhaps as
early as
spring of 2010.
The same type of vector has been successfully tested in both animals and
humans for
a similar type of early-onset retinal degeneration called Leber's congenital
amaurosis.
Additional investigators include William Hauswirth, PhD, at the University
of Florida,
Gainesville; SriniVas Sadda, MD, at Doheny Eye Institute, University of
Southern
California; Emad Abboud, MD, and Hisham Alkuraya, MD, at King Khaled Eye
Specialist
Hospital, Saudi Arabia; and Peiquan Chao, MD, PhD, Department of
Ophthalmology, Shanghai
Jiaotong University.
Source:
Debra Kain
University of California - San Diego
Updated 14.10.09
