| From the Los
Angeles Times
The controversial technique could eventually
help people with blindness caused by such vision disorders as macular degeneration
and retinitis pigmentosa.
By Thomas H. Maugh II
Los Angeles Times Staff Writer
April 28, 2008
For the first time, researchers have used gene
therapy to increase light sensitivity and improve vision in patients who
were virtually blind, a finding that offers new hope to hundreds of thousands
of patients with inherited forms of vision impairment.
Although the patients had a rare form of blindness
called Leber's congenital amaurosis, researchers believe the approach can
ultimately be used for a broad spectrum of disorders, including retinitis
pigmentosa and macular degeneration.
The experiments, so far meant only to prove
the safety of the technique, produced 'real clinical benefit' and 'made
a real difference in patients' lives,' said geneticist Robin R. Ali of
University College London, the senior author of one of two reports presented
Sunday at a Fort Lauderdale, Fla., meeting of the Assn. for Research in
Vision and Ophthalmology.
The reports were published online Sunday by
the New England Journal of Medicine.
'The fact that they had patients who could
now read lines on an eye chart . . . and one who could run an obstacle
course -- this is a really great advance,' said geneticist Stephen Rose,
chief research officer of the Foundation Fighting Blindness, who was not
involved in the research. 'This has changed the landscape of hope for patients.'
Technique controversial
Added Dr. Morton F. Goldberg, an ophthalmologist
at John Hopkins University's Wilmer Eye Institute: 'In the field of retinal
dystrophies, this is, I believe, the most important therapeutic discovery'
in four decades. 'It's a landmark.'
The results are particularly important because
gene therapy, in which a defective gene is replaced with a good one, has
been 'a snakebitten field,' with at least two subjects in other experiments
dying and a few others developing cancer, said Dr. Albert M. Maguire of
the University of Pennsylvania School of Medicine, lead author of the second
report.
A handful of children with severe combined
immunodeficiency disease were successfully treated, but critics charged
that conventional treatments would have been equally effective -- and safer.
In France, three children treated for the disease developed leukemia because
the delivery agent inserted the new gene in the wrong place.
Researchers have reported modest benefits
for Parkinson's disease, but no gene therapy results have been as dramatic
as the Leber's findings.
'We have been working for years, and it
has really been rough,' Maguire said. 'Here we finally have something
in a curable disease that really seems to be working.'
Leber's congenital amaurosis affects about
3.000 people in the United States and perhaps 130.000 worldwide. Sufferers
are born with severely impaired vision that deteriorates until they are
totally blind in childhood or adolescence. There has been no treatment
for it.
What makes Leber's a good candidate for gene
therapy is the fact that most of the visual apparatus, including the retina,
is intact, at least at birth. Typically, the defective gene that produces
Leber's is one of several in a pathway that produces chemicals for the
eye to generate an electrical signal to the brain.
If that gene can be replaced before the visual
apparatus deteriorates from lack of use, then vision can be restored, Maguire
said.
Hope beyond Leber's
That basic strategy could be used to treat
a variety of congenital retinal disorders. 'With an aging population,
one of the most serious problems that hinders old people is the loss of
sight,' said Dr. Katherine A. High of Children's Hospital of Philadelphia
and a coauthor of one of the studies.
Retinitis pigmentosa -- the broad family of
disorders that includes Leber's -- affects an estimated 100.000 Americans.
Macular degeneration affects 1.25 million Americans, and the number is
expected to grow to 3 million by 2020 as the population ages.
Those conditions are caused by other defective
genes, but the treatment principle would be the same. Researchers would
have to design a specific delivery vehicle, or vector, for each disorder
bearing the proper gene.
In the latest experiments, both groups of
researchers used a gene called RPE65 that is defective in many Leber's
patients. Both groups also used as a vector a small adeno-associated virus
that infects humans and other primates but is not known to cause disease.
Its safety has been shown in various gene therapy experiments.
The Pennsylvania group's vector was developed
by High; the British group used one produced by Targeted Genetics Corp.
of Seattle.
The Pennsylvania group treated two 26-year-olds
and a 19-year-old. Between October and January, Maguire injected a bit
of the vector below the retina into each patient's worse-damaged eye.
Two weeks after the injections, all three
patients reported improved vision in the injected eyes, Maguire said. By
gauging pupillary response to light -- researchers' only objective measure
of vision -- they found that light sensitivity had improved about threefold.
The treatment also reduced nystagmus, an uncontrollable roaming of the
eye common in blind people.
The patients also performed better on more
subjective tests. One patient's vision on an eye chart, for example, improved
from 20/640 to 20/290, about 3 1/2 chart lines better, according to Dr.
Jean Bennett, lead author of the study. The Food and Drug Administration
requires three lines of improvement to consider a treatment effective.
No ill effects found
The therapy did not produce inflammation in
the eye or any other toxic side effects, the researchers said. One patient
did develop a small hole in the retina that they suspect was a result of
the surgery, but it did not interfere with vision.
'All three subjects are asking if they
can have their other eye injected,' High said. 'That's a pretty
good indicator of its effectiveness.' The current research protocol
does not allow for that, however. |
The researchers have no idea how long the
improvements will persist, but dogs given the treatment have remained stable
for at least eight years, she said.
The British group also treated three patients,
using slightly smaller doses of the vector. They also found no ill effects.
Their patients did not have improved visual acuity, but one of them, 18-year-old
Steven Howarth, had improved light sensitivity, especially at night.
'My sight when it's getting dark or it's
badly lit is definitely better,' he said in a statement. 'It's a
small change -- but it makes a big difference to me.'
Howarth is 'staying out later and more
confident at night,' Ali said.
Both groups are now increasing the vector
dosage and moving toward younger children whose visual apparatus is less
deteriorated. Ideally, High said, the treatment would start when the disorder
was diagnosed in children.
thomas.maugh@latimes.com
Gene therapy treats blindness
This weekend two teams reported success in
helping people to see again. Nature News catches up on the state of gene
therapy trials against blindness.
Kerri
Smith
Seeing the light: gene therapy helped this 18-year-old to see better
in dim light.AP
What sort of blindness do the new reports address?
Two separate teams have published reports
of successful gene therapy trials for a type of Leber's congenital amaurosis
(LCA), a rare inherited form of blindness. Patients with LCA have a genetic
defect that affects the development of the light receptors in their eyes;
typically they have poor vision at birth and are blind within three decades.
Some 3.000 people are thought to be affected in the United States.
Were the patients 'cured'?
In one study, led by husband and wife team
Jean Bennett and Albert Maguire at the University of Pennsylvania in Philadelphia,
three patients received the treatment and all three showed some improvements
in vision1: they went from being able to detect hand movements to being
able to read lines on an eye chart, the team reports.
In the other study, a team based at London's
Moorfields Eye Hospital and University College London also treated three
patients, and were able to help an 18-year-old man who had extremely limited
vision in poor light conditions; trials in a dimly-lit maze showed his
vision had markedly improved. This despite the fact that the trial's primary
aim was to assess the safety of the therapy, and not its clinical effects2.
"What we were really surprised by was that we saw a clinically significant
effect," says Robin Ali, who led the study. Both reports appear in
the New England Journal of Medicine 1,2.
How does it work?
The idea of this type of gene therapy is to
insert a normal copy of a gene into cells that have a faulty or missing
version, restoring the cells' normal function. In the type of LCA the two
groups studied, a gene called RPE65 is mutated, making light-sensitive
cells in the eye unable to capture light and transmit information about
it to the brain. In early stages it mainly affects the group of photoreceptors
referred to as rods, which are more numerous and more sensitive to light
than those sensitive to colour. In the new studies, both groups got the
RPE65 gene into the retina by packaging it inside a harmless virus and
then injecting this virus into the eye. When the virus 'infects' retinal
cells, the gene is transferred and can theoretically start functioning
normally. This should allow the right proteins to be made for functioning
photoreceptors, providing that the retinal cells are still alive for the
gene to be active within.
Has gene therapy been trialled for blindness before?
Yes, but for a different type of blindness,
and using a different mode of action. Another eye disease called age-related
macular degeneration, in which blood vessels grow across the eye and obscure
vision, has been targeted with a technique that silences a particular gene
(as opposed to inserting one). In 2006, a clinical trial of a drug called
Bevasiranib demonstrated that interfering with a gene called VEGF reduced
blood vessel growth and could improve vision slightly in such cases. Gene
therapy has also been tried for a type of eye cancer called retinoblastoma.
What other treatments are being investigated for severe blindness?
Blindness has many different causes, so there
are several molecular treatments being pursued. In a paper published in
Nature Neuroscience this week, for example, Botond Roska at the Friedrich
Miescher Institute for Biomedical Research in Basel, Switzerland, and his
team improved vision in blind mice that had lost all their photoreceptors
by inserting a light-sensitive protein derived from a green alga into their
eyes3.
Ali is confident that we'll see more of his
technique as it progresses through clinical trials. "This study paves
the way for the use of the same technology for other inherited forms of
retinal degeneration," he says. They are currently trialling it in
another 9 patients and hope to be close to licensing the method in about
2 years.
References
1. Maguire,
A. M. et al. N. Engl. J. Med. doi:10.1056/NEJMoa0802315 (2008).
2. Bainbridge,
J. W. B. et al. N. Engl. J. Med. doi:10.1056/NEJMoa0802268 (2008).
3. Lagali, P. et al.
Nature Neurosci. doi:10.1038/nn.2117 (2008). |
