A computer modeling study suggests that administering the drug
ranibizumab is associated with reducing the magnitude of legal blindness
and visual impairment caused by age-related macular degeneration in non-
Hispanic white individuals,
according to a report in the June
Archives
of Ophthalmology.
To estimate the number of individuals in the United States who may
benefit from treatment with ranibizumab to treat neovascular AMD and
prevent AMD-related blindness,
Neil M. Bressler, MD, of Wilmer Eye
Institute at Johns Hopkins University and colleagues designed a modeling
study using outcomes from three previous Phase III ranibizumab trials.
Using statistics from the Beaver Dam Eye Study and data from the 2008
U.S. Census Bureau, the model predicted that 151,340 non-Hispanic white
individuals in 2008 would develop neovascular AMD. Using data from the
Age-Related Eye Disease Study, the authors estimated that one-third of
these cases (51,000 individuals) would already have preexisting
choroidal neovascularization in the opposite eye, making those patients
ineligible for the model used in this study. Of the 151,340
individuals, the authors estimated that ranibizumab would be accessible
to 103,582 individuals, making them eligible for inclusion in the
study’s modeling criteria.
Based on the model designed for the study, if no treatment were given to
the 103,582 cases for which monthly ranibizumab was indicated and
accessible, 16,268 (16 percent) would progress to legal blindness in two
years. The authors estimated that monthly ranibizumab usage would
reduce the incidence of legal blindness in two years by 72 percent, to
4,484 individuals. Additionally, based on the model designed for the
study, if no treatment were applied to the 103,582 cases for which
monthly ranibizumab is indicated and accessible, 34,702 (34 percent)
would progress in two years to visual impairment (worse than 20/40 in
the better-seeing eye, a level that precludes an unrestricted driver’s
license in most states). The authors estimated that monthly ranibizumab
usage would reduce the incidence of visual impairment in two years by
37 percent, to 21,919 individuals.
Based on results of the model designed for this study, the authors
conclude that ranibizumab would have an effect on reducing the
occurrence of visual blindness in individuals with AMD when treatment is
administered on a monthly basis when available.
‘Natural Killer’ Cells Tied to Dry- Eye Inflammation
New research discovery published in the
Journal of Leukocyte Biology (
jleukbio.org) offers hope for new Drugs that treat the cellular cause
of the dry-eye disease rather than its symptoms. That’s because the
research is the first to identify natural killer cells, a type of cell
that provides innate immunity to the eyes, as promoting the inflammation
that plays a critical role in the development of dry-eye disease.
“Dry-eye disease is suffered by millions of people in the U.S. but still
lacks effective management,” said Yihe Chen, MD, a researcher involved
in the work from the Schepens Eye Research Institute at the
Massachusetts Eye and Ear Infirmary of the Department of Ophthalmology
at Harvard Medical School in Boston.
“Our study has promoted the further understanding of the pathogenesis of
dry-eye disease, which is fundamental to develop new treatments and
thus improve quality of life for those with this disease.”
To make their discovery, the scientists tested two groups of mice. The
first group was normal and the second group was depleted of natural
killer cells. When both sets of mice were induced with dry-eye disease
under the same conditions, the disease was less severe in the mice
depleted of NK cells than the normal mice. This suggests that NK cells
play a pivotal role in the development and severity of the disease,
making them a target for the development of new drugs.
Progress in Using Stem Cells to Reverse Blindness
Researchers have used cutting-edge stem cell technology to correct a
genetic defect present in a rare blinding disorder, another step on a
promising path that may one day lead to therapies to reverse blindness
caused by common retinal diseases like macular degeneration and
retinitis pigmentosa.
In a study appearing in an advance online publication of the journal
Stem Cells on June 15, 2011, investigators used recently developed
technology to generate induced pluripotent stem, or iPS, cells from a
human patient with an uncommon inherited eye disease known as gyrate
atrophy. This disorder affects retinal pigment epithelium cells, the
cells critical to the support of the retina’s photoreceptor cells, which
function in the transmission of messages from the retina to parts of
the brain that interpret images.
“When we generate iPS cells, correct the gene defect that is responsible
for this disease, and guide these stem cells to become RPE cells, these
RPE cells functioned normally. This is exciting because it
demonstrates we can fix something that is out of order. It also
supports our belief that in the future, one might be able to use this
approach for replacement of cells lost or malfunctioning due to other
more common diseases of the retina,” said lead study author cell
biologist
Jason Meyer, PhD, assistant professor of biology in the School
of Science at Indiana University-Purdue University Indianapolis.
Because iPS cells can be derived from the specific patient who needs
Them, use of these cells may avoid the problem of transplant rejection.
In the study, vitamin B-6 also was used to treat the damaged RPE cells
producing healthy cells that functioned normally. The retina is a
relatively easily accessible part of the central nervous system, which
makes it an attractive target for correction with iPS cells.
Researchers are hopeful that once the gene defect responsible for a
blinding disorder is corrected in iPS cells, these cells may be able to
restore vision.
Next Generation Gene Therapy
Inspired by earlier successes using gene therapy to correct an inherited
type of blindness, investigators from the University of Pennsylvania
are poised to extend their approach to other types of blinding
disorders.
In a previous human trial conducted at the Children’s Hospital of
Philadelphia and Penn, researchers packaged a normal version of a gene
missing in Leber’s congenital amaurosis inside a genetically engineered
vector, called an adeno-associated virus (AAV). The vector delivered
the gene to cells in the retina, where the gene produces an enzyme that
restores light receptors.
The results from three Phase I clinical trials for LCA showed the
potential for gene therapy based on adeno-associated viruses delivering
corrective genes to the retina,” notes co-senior author
Jean Bennett, MD, PhD, the F.M. Kirby professor of ophthalmology. “To broaden
treating inherited eye diseases, we will need a larger vector toolkit,
and what we have seen of AAV8 gives us hope for creating gene therapies
for diseases that attack the retina’s photoreceptors. This preclinical
study provides the guidance we need to formulate dose level and type of
vector to deliver corrective genes to treat blindness caused by the loss
of photoreceptors.”
In the present study, published in
Science Translational Medicine, the
Penn team compared the safety and efficiency of delivery in an animal
model of two different types of AAVs—AAV2, which was used in the human
trials for LCA, and AAV8, a second-generation AAV technology initially
discovered in the lab of co-senior author
James M. Wilson, MD, PhD,
professor of pathology and laboratory medicine.
The researchers used both vectors to deliver a green fluorescent protein
transgene to the retinal pigment epithelial cells and photoreceptor
cells of nonhuman primates.
“We showed that we can use AAV8 to deliver genes to the photoreceptor of
the primate eye at lower doses, both safely and efficiently,” says
first author Luk H. Vandenberghe, PhD, senior investigator.
Both AAV2 and AAV8 delivered the gene safely and efficiently to the
monkey retinas, but AAV8 was markedly better at targeting photoreceptor
cells.
The STM study describes the dose relationship between AAV2 and AAV8
vectors and their target cells and the immune response in the nonhuman
primate retina. From this the researchers found dosage thresholds To
safely and efficiently target cells in the outer retina such as RPE
cells and rod and cone photoreceptors. While AAV2 and AAV8 efficiently
delivered the gene to RPE cells at moderate to low doses, expression of
the GFP gene in rod and cone photoreceptors was reached only at higher
dosages. Substantial delivery to rods was obtained with moderate doses
of AAV8, doses similar to those currently used in experimental clinical
protocols.
The vectors at intermediate doses did not cause problematic immune
responses and post-surgical injection complications. The delivered gene
also stayed in the retina at very high levels throughout the study
duration of four months. Additionally, the GFP gene was preferentially
transduced to one type of retinal ganglion cells, which surprised the
researchers. In general retinal ganglion cells transmit visual
information from the retina to several regions of the brain. This
knowledge could be used in the future to further delineate the neuronal
connections between the retina and the brain.
In earlier animal studies, AAV8 also delivered genes safely and
efficiently to the mouse retina. However, the mouse retina differs
significantly from the primate retina, most notably in structure, which
affects the surgical approach to delivering corrective genes to
different parts of the eye. The present study in nonhuman primates is
the next step to better translate treatment strategies for people.
“To address patients with other retinal diseases, we need a renaissance
of technology—new and better vectors to safely and effectively deliver
corrective genes to a range of diseases,” says Dr. Wilson. “My lab has
recently isolated new families of simian-based adenoviruses and
adeno-associated viruses. Recombinant versions of these viruses are
turning out to be useful as improved gene transfer vehicles to a variety
of targets