Ophthalmic Genetics and Clinical Treatment Opportunities – Paul Sieving

Paul Sieving:
Thank you for that kind introduction, and greetings to several of you in the audience
whom I know in the practicing community here of ophthalmology in Washington. It’s actually
a very vigorous and vital dynamic practice of eye and vision care. I’d like to spend a few moments this morning
talking about ophthalmic genetics and actually what is now happening in the application of
that to care. Let’s see if this works. There it goes. Some presentation objectives, I will
briefly review some of the history of where genetics has come from historically, and you
will, by the end of this, be seeing a number of ophthalmic photos of various eye diseases,
the phenotypes. And then to consider where ophthalmology is going to be incorporating
gene discovery in therapeutics. Eye disease in a big hospital like this at
Suburban may not seem to have center stage, but, in fact, eye disorders collectively rank
in the top ten of the maladies that affect us as humans, according to WHO just a few
years ago. Obviously, we see eyes all the time. I’m looking at a lot of eyes looking
at me. And you see yourself in the mirror in the morning. Then when you’re looking at
the eye, you’re looking at the external anterior segment, the eyelids, pupils, sclera, iris.
But hidden at the back inside are some vital elements of vision. The neural retinal tissue,
the red lining here back, red because of the molecule that is light sensitive, rhodopsin.
At the center of the action, the macula, you’re looking at the slide with your macula. It’s
the fine focus center of vision. There are several major diseases. Here we
see three of the four major diseases, the eye cataract. A lot of cataract surgeries
are going to be done in the Bethesda and Washington community today. And glaucoma. Glaucoma straddles
the front of the eye. Glaucoma straddles the front of the eye, where pressure can build
up because of an outflow obstruction of fluid, and that pressure, for reasons that are rather
indecipherable still at the moment, ultimately affects the optic nerve, which contains the
axons of the 100 million rod and cone photoreceptors in the retina. And then macular degeneration,
which is the scourge of vision. What is not shown here is diabetic retinopathy, the effect
of diabetes on the major blood vessels that line the back of the eye. But that’s the way we look at the eye when
I was a resident, 30 some years ago. Now we look at the eye as tissues and cells. All
of these cells, the light sensitive rod and cone photoreceptors, the rods containing that
rhodopsin that imparts the reddish color to the retina, and the cones which come in three
flavors, red, green, and blue, and give us the full spectrum, chromatic spectrum of vision
that we all enjoy. Now, medicine is moving to cells. These cells
have obviously been there a long time in the textbooks, but now we’re actually dealing
with these on a rather medically personal level, and I’m going to tell you some stories
about rod and cone photoreceptors. But back on the thread of genetics in general
in eye disease. Here are six photographs. These are the kinds of patients who will be
seen in the Washington community today, individuals with cataract. This is a particular special
cataract. You can see three white punctate dots of cerulean cataract. This young child
with the one eye is looking right straight at you, but with the other eye is rather askew,
strabismus, muscle surgery, pediatric ophthalmology. The front here, the iris looks good until
you can see that it’s not attached at the base. It’s — there’s a dehiscence, an iris
coloboma, a developmental issue. And at the bottom, three views of the back of the eye,
age-related macular degeneration, a sheet of blood on the back of the eye through which
vision is going to be distorted. And when this blood consolidates and tears up the neural
retinal tissue, obviously the vision is going to be impaired significantly. Or glaucoma,
the enlarged yellowish center missing the axons because of elevated pressure in the
eye. And macular degeneration of the Stargardt flavor, Dr. Stargardt, German, two centuries
ago, an overt genetic problem of vision, but, in fact, all of these have a genetic issue
going on. So the public health impact of all of this
vision impairment is considerable. Tens of millions of our fellow citizens suffer vision
impairment due to diseases that have either a direct genetic basis or result in part from
genetic risk. And as we have birthdays every year, the incidents of age-related eye diseases
is increasing at an obviously large cost to us as individuals and to society. So, while
eye care is well advanced, in fact we need to have more effective therapies. Let me just tell you how I’m going to be using
words today. Genes, genetics, genomics, and medicine; they flow together. Genes: the biologic
code. Genetics: the play-out of those genes let’s say in families, inheritance in families
and ultimately affecting society. Genomics: how the gene product, the product that the
gene makes, affects cells, and, ultimately, what the mechanisms of cell processes are
and how that plays out in disease and medicine, the treatment of disease. That’s what we and
you will be doing here today at Suburban. And what we have seen is that we started with
genes and we’re now squarely in the camp of medicine. But let’s roll the clock back two and a half
millennia. Hippocrates, blue eyes are inherited. Now that’s an interesting idea. Or, speaking
in Greek, so I’m translating, squinty-eyed children have squinty-eyed parents. When a
nearsighted person squints through narrowed eyelids, you perceive a little bit better,
and if you look at the kids who are nearsighted, you will find that, quite frequently, the
parents were nearsighted. Or, Aristotle, 50 years later, further described myopia and
he recognized that blindness can be transmitted between parent and child. And that was an
idea picked up later on by Plutarchos, speaking of the biblical, Isaac and Jacob, both of
whom had older age vision loss, and he had the concept of heredity old age blindness.
It was that macular degeneration. Now speeding up the clock and going back to
1770, Lort & Dalton recognized that color deficiency runs in families and it is us poor,
feeble men who suffer it as opposed to women. That’s because the color genes are on the
X chromosome and men have only one, whereas women have two X chromosomes. And when the
men have the color deficiency on one, there’s nothing to mask it, whereas the women have
a second copy that usually has a normal color gene on it. And then a century later, Horner
recognized that quite frequently men who are color blind had uncles, mother’s brothers
who were color blind, speaking of X chromosome inheritance. And then going a century further,
just a few decades ago, Jeremy Nathans cloned one of the genes that imparts light sensitivity
and ultimately color vision, but not with rhodopsin, but with the color opsin genes,
rhodopsin and the color opsins. And so if we look at that year, 1983, when
rhodopsin was cloned, there were few genes that were captured. But across the three-decade
span, the vision community has been extraordinarily vigorous in identifying genes related to eye
disease. And now there are some 600 genes that are known; 200 that affect the retina,
nearly 200, 150, 200 that are affecting the lens and the cornea at the front of the eye.
The eye turns out to be, unfortunately, very rich in monogenic traits in which a single
gene causes a vision problem. In fact, still about 20 percent of the identified human disease
genes involve the eye and vision. So, when we have all of these hundreds and
hundreds of genes, what difference does it make? Well, we, we — medicine, science, vision
research — we are now imparting on the new frontier of addressing these problems at the
gene level. In a moment I will tell you about RPE65, a molecule that causes LCA, leber congenital
amaurosis, but let me defer that for a moment. In this case, however, there is a defective
gene, actual both copies, both alleles in the gene are defective, and by providing an
external normal copy, one can restore the cellular function that depends on RPE65. Or,
in the case of parent to child direct transmission, the dominant transmission, one may — in fact,
in animals you can, but in humans may be able to suppress that one copy that’s defective,
and allow the second normal copy to function throughout life and retain vision. So you’d
have to suppress the mutant gene, or repair it, or just go around the whole system. Don’t
worry about the gene, but deliver some other product that is therapeutic. Let me turn back to this RPE65 for a moment.
The story starts in 1869, when Dr. Theodore Leber saw several children who were blind.
They were born blind, severe vision loss. They had bobbing eyes, nystagmus movements,
the sign of congenital severely impaired vision. And a century later when the electroretinogram
was invented or identified, used, that the responses were found to be non-detectable.
The electroretinogram is similar to the electrocardiogram, but in this case it’s for the retina, the
neural tissue in the eye, and that tissue was not functioning. These are pictures that
I was taught when I was a resident 30 years ago. You look into the eye and sometimes you
see nearly nothing, but the child is not seeing. Other times you look in and you see darker
spots of injury pigment from injury to cells in the eye, or you see a dissolution of breaking
up of the neuroretinal tissue. So this is LCA, leber congenital amaurosis, Dr. Theodore
Leber’s congenital blindness, LCA. This is LCA as I was taught it in the premolecular
era. This is now LCA, 19 genes and counting. These
genes are functioning at the level of the rod and cone photoreceptors and the supporting
tissue called the retinal pigment epithelium, and these 19 genes, in fact, are playing right
here. And the one that I’m going to focus on, RPE65, is involved in the vitamin A cycle.
Eat your carrots. Grandma was right. If you don’t eat enough carrots, you’re going to
have vision problems because you need vitamin A, and, in fact, there are enzymes specifically
at the back of the eye that process dietary vitamin A and make it available in the proper
molecular configuration to function for vision. So let’s return to RPE65, the molecule, and
go about a decade and a half ago. Mike Redmond, working just across the street in a laboratory
in the National Eye Institute, was looking at the genes that are abundant, or, actually,
the proteins that are abundant in the retinal pigment epithelium, RPE, and there was one
with a molecular weight of 65, so it gets the name RPE65 protein. He cloned the gene
for it, and everybody admired his technical prowess. He’s got a new gene. What does it
do? Nobody knew. Five years later, Mike knocked out the gene in a mouse, and the mouse was
blind. So we know that RPE65 is critical for vision. Rather crude way of finding out, but
very effective. At the same time, in Australia, humans were
found by a geneticist, humans were found to have mutations in the RPE65 gene, and they
were blind. In fact they had LCA, leber congenital blends. And then the story moved to Sweden
where a dog was found, the Swedish Briard dog was found to have mutations in this gene.
And then the story speeded up quite a bit. Here is one of the dogs, a Swedish Briard
dog. Actually that’s not I’m told a Swedish Briard dog, but the gene was put into the
dog so that this dog, cross-bred, et cetera, but this dog was blind from RPE65. And then
within a matter of 1998 to 2001, just in the space of a couple of years, gene therapy was
done to put the normal RPE65 gene into this dog, and a couple of weeks later he could
play Frisbee with you. Obviously, great story to take down to Congress. Everyone loves dogs.
Everyone loves genetic stories. So he is our best ambassador for vision. Literally, Senator
Harkin has met him, et cetera. Well, looking at the electroretinogram function,
a complex slide but not that difficult, panel one, two, and three, middle panel, flat responses.
This panel, a big wave forms in a normal, in a normal, compared to this dog before treatment.
No action. This is very dim light and very bright light. A flash of light startles the
neurons and gives you these wave forms. And you light big, and don’t you light flat, and
the dog is flat, but when you put the gene in, RPE65 gene, look what comes back, and
that’s why the dog can play Frisbee with you. In fact, the dog tells you it’s got vision
and the electrical function says it has vision. Well, from 2001, it was just a major step,
about only a few years before gene therapy was done for kids who had LCA from RPE65.
And that was recognized by Science Magazine a year later, in 2009, as a seminal event
in science and medicine. It was only the runner up. I don’t remember what the winner was,
but I think it should have been the winner. Here is Al McGuire, one of the authors on
the first report of treating these kids with blindness, and he is treating a young man,
injecting the gene into the eye. Let’s just look at what that really means to treat an
eye genetically. What he is doing here in cartoon is to take a very narrow needle, fine
needle, and put it through the eye wall, underneath the retina, inject some fluid. It contains
the vector. Make a little bubble, or here another illustration of bubble. Here are the
rod and cone photoreceptors. Here is the retinal pigment epithelium, where the gene resides.
So he puts the fluid next to those RPE cells, provides the gene, ultimately, and this child
is now playing baseball. Well, this is — that was RPE65, one example
of gene therapy for vision, and there are many others. Stargardt macular degeneration;
I mentioned that, showed you a slide right at the outset, Dr. Stargardt. We know the
gene. It’s ABCA4, and there is a company, Oxford Biomedica, which is quite vigorous
in working in gene therapy. In this case they are using lentivirus, because this gene ABCA4
is a monster. It’s huge. It has nearly 60, 6-0 axons. It’s a big, big gene. It doesn’t
fit in most delivery vectors. So you turn to something that can carry a cargo, the lentivirus,
and they have a trial going on StarGen, just started recently. Here’s another one. Usher Syndrome, children
born deaf and rapidly going blind such as by age 20, they really have negligible residual
vision; also a big gene, and they have a trial going on for Usher Syndrome. Or — and these
are direct. These are direct gene therapy, these two trials. Or, somewhat indirectly, using the same delivery,
the lentivirus, but delivering therapeutic vectors, therapeutic molecules, endostatin
and angiostatin, delivering the gene makes the protein. And the protein rescues the function
of macular degeneration diabetic retinopathy causing new blood vessels, neovascularization
of the retina. And, in aggregate, the vision community is
quite vigorous in working the area of gene therapy, leber congenital amaurosis. RPE65
started the ball rolling. Here is Usher syndrome and Stargardt’s soluble flip. Many of these
currently are being done outside the U.S., but we expect that they will be moving here
into the states soon. What else do you do with genes? You’ve got
genes. What do you do with them? Well, how about using them for medicine, to inform people
of their fate? Here is an interesting story that I would commend to you, New York Times,
July 9, last summer, and this is for ocular melanoma. You can read it online, Cassandra
Canton [spelled phonetically], age 18, noticed a vision problem, went to her ophthalmologist
who said, “Cassandra, you’ve got a problem. You’ve got a tumor. You’ve got a cancer in
your eye. It’s growing. It’s broken up the retina. We’re going to have to do something.
In this case, the doing something literally is to remove the eye, the nucli [spelled phonetically],
the eye, because you can’t contain this cancer. You take it out at the source, take the eye
out, put in a prosthetic shell so that, cosmetically, you and I wouldn’t notice. But, obviously,
you’re losing an eye, Cassandra.” Well, ocular melanoma, melanoma, skin melanoma,
it’s a pigment cell condition. So, it is the pigmented uveal tissues of the eye. Here,
at the front of the eye, the iris has pigmented tissue, and you can see the iris melanoma,
kind of fluffy, elevated. It’s a growth on the iris; bad, bad, bad sign. That eye is
in serious jeopardy. We’re looking at the back of the eye, here is a tumor, a melanoma,
a ball of melanoma growing underneath the retina. About 2,000 Americans will be newly
diagnosed this year, and half of them are going to die from metastases. But the story becomes extremely interesting
for these patients, but also for all of cancer, by the work of an ophthalmologist, Bill Harbour,
working at Washington University Saint Louis, who collected these cases and began to do
proteomics on them, and sorted out the cases as people who didn’t die and people who did
die, and compared those, and came up with a critical difference. People who died, he
found, had mutations, an alteration of the BAP1 gene in 84 percent of metastatic tumors.
BAP1 breast cancer, BRCA1, associated protein 1. And his findings suggested that BAP1 suppresses
metastases. And so if you — it’s a negative, double negative statement. If you make mutations
in this, you cause metastases. So, if we — and this paper published in 2010 was rapidly turned
into a medical diagnostics test by Castle Biosciences in 2011, and you can order it
here in Suburban. Turning back to Cassandra, the question now
is which class is she, Class 1 over the span of five and six years. They don’t die, and
this is a composite of several hundred cases of ocular melanoma. Or is she in Class 2 with
a median survival of just over 40 years? Turns out, read it online, she has Class 1. She’s
all set. But the second part of that same story is another individual who falls in this
class. That is medicine, folks. You can’t always fix things, as some of us know, but
you have to work with patients and give them information that they can act on, and I think
this is first class medicine. But what about this rumor that people don’t
want to know what they’ve got. Let’s stick our heads in the sand. Don’t think so. People
want to know about the genetics in their family. These, I make a joke, are two of my favorite
magazines, and in one year, 2007, Science has human genetic variation, breakthrough
the year, and Wired Magazine says, “Your life decoded.” People are very interested in their
genetic status. So, how does ophthalmology deal with this?
We’ve got 600 genes to deal with, and we’re just scratching the surface. How do we deliver
on the promise of diagnostics and genetics for people at a time when opportunities are
expanding? How do we handle the large variety of these infrequent monogenic diseases in
which one gene is converted into a disease? Several years ago the Eye Institute initiated
a project called eyeGENE, because several years ago there were boutique laboratories,
research laboratories that were doing genetics for one or two genes. If you are interested,
just go back to your computer and Google eyeGENE, and this will come up so you can get the information
yourself and participate if you wish. It’s a national network of the boutique laboratories
that, in aggregate, are testing 35 genes — excuse me, about 100 genes for 35 diseases. And the
scheme here, this is under the National Eye Institute, so our scheme is yes, it’s important
to provide diagnostics to people in genetic information, but it’s also critical for research
to know the medical characteristics of those people. This slide breaks out into three parts, the
patient and the physician, part one, sends a sample to coordinating center, and Kerry
[spelled phonetically], I see you sitting there, Kerry, raise your hand. Kerry is running
that right across the street. And the center sends it, distributes a sample to one of many
laboratories that are boutique research laboratories at the moment. They’ve got special expertise
in your gene, if that’s what you need. Information comes back, goes back to the patient. That’s
medical care. At the same time, the individual signs a consent right up front that says,
“Anonymize my information. Keep it safe, but use it.” Use it for research so that we can
understand what these diseases are and how to proceed. So we’ve got a unified medical
care research venture going. It has a registry, consents, contact information, the phenotypes,
meaning the medical characteristics, the genotypes, the gene level, and a repository of samples.
It has been well-received across the country; all but five states have participating sites.
I keep telling Kerry to take a site visit to Vermont to encourage them. She wants to
go to Hawaii and Alaska instead. [laughter] And we’re enrolling about 1,000 patients a
year. I think, Kerry, that’s your saturation point. A lot of hands-on work, but the importance
is to couple what happens in this hospital, the medical venture of patient and physician
medicine, to get that information put together with the genotypes, so that we can move on
with understanding the interplay between phenotypes and genotypes. Diagnostics is moving on, as we all know.
Now we’re at the level of sequencing the entire human genome for individual patients, and,
particularly, with Suburban coupled to Johns Hopkins. This is state-of-the-art medical
care. It’s tricky because the information is so vast, 20,000 genes you’re looking at,
or something. The information is so vast that it becomes an analytics problem and not a
cost of sequencing problem. The cost has dropped over the past six, seven years from $1 million
for your genome to $1,000 for your genome. So, it’s not — that’s not the cost. The cost
is the analytics and the medical information to extract from that. Ophthalmology has been front and center in
this. This is a page 2010, Science Magazine, “Affordable ‘Exomes’ Fill Gaps in Rare Diseases.”
Yes, a lot of our diseases are rare diseases, whether they are cardiology diseases or ocular
diseases. In this case what was featured was the Lidsky family, Betty and Carlos, four
wonderful kids born with vision, no problem. Unfortunately, three of them are now blind.
And despite all of these boutique laboratories in vision looking for this gene, and the Lidsky
family living in Miami, it was elusive until a group just shot-gunned the human genome
in this family and came up with a new gene, DHDDS. It turns out to be an enzyme that puts
sugar groups on the rhodopsin molecule clone, the rhodopsin molecule I mentioned was cloned
by Jeremy Nathans in 1983. And without those sugar groups, the rhodopsin molecule, the
light sensitive molecule of the eye doesn’t function, and so the kids lose their vision.
And now therapy ideas are moving forward in animals for DHDDS. So far, I have spoken only of these single-gene-causes-you-the-problem
diseases, single gene diseases, monogenic diseases, Mendelian, Gregor Mendel diseases.
But there’s a whole world of patients seen in this building who have what are called
complex genetic diseases. In general, these are most common that affect us, and they are
due to risk factors that ultimately impair together, collectively, impair cell function
and cause disease to happen. Most common of those blinding conditions for
ophthalmology is age-related macular degeneration, AMD. And at the bottom what was unfolding
was a panoply of pictures, a normal fundus, the optic nerve, the blood vessels, the macula,
the reddish retinal tissue. And with aging, a number of individuals developed these spots.
They’re lipid accumulations. They’re debris accumulations. They’re called drusen. And
those drusen predispose, heavily predispose, to one of two things; either atrophy, death
of tissue, or hemorrhage. And for either of those, when you have this in the center of
your vision, you can’t see through it. You are blind, legally blind, at least 2,200,
from loss of central vision. You’ve got your peripheral vision. You can get around. But
you can’t drive. You can’t play cards. You can’t watch TV. You can’t read. Two million
Americans are already legally blind from AMD. Many more are at risk and we’re all getting
older, so let’s get on with the show and do something about it. But this is a complex
disease. There’s no single gene to be looking for. You’ve got to look for the risk conveyed
by a gene, and, in fact, well, here’s to use just an illustration of — cartoon form of
the havoc this causes with vision. And then a similar event happened just a few
years ago, 2005, when five groups simultaneously identified the CFH gene, compliment factor
H gene. Just a parenthetic, I love being part of the vision community. We don’t do it one
time. We do it five times. You worried about is this report true or not? Well, this article
of this issue of Science has three independent groups publishing the same gene, identifying
the same gene for AMD. And I would congratulate Emily Chew sitting here, who, with Rick Ferris
and John Paul SanGiovanni at the Eye Institute were front and center in the Klein article
of the CFH gene. So, what does this tell us? It’s only a gene.
Well, this tells us a lot. This is the complement cascade system, the immune system of the body,
and, within a year, two more complement components. Factor B and complement component C2 came
on the scene, more risk factors for AMD. This says that AMD is a cousin of other chronic
diseases that have a play with the immune system: Alzheimer’s, Parkinson’s, cardiovascular
disease. These are cousin diseases and invoking the surveillance mechanisms of the body. And,
quite remarkably, if you add up these three genes, 74 percent of the risk of developing
AMD is accounted for. These are heavy, big players. Here is a schematic, simplified schematic
of the complement cascade system. CFH, sitting in the middle, plays in all three pathways.
Here is C2. Here is C7. Here is Factor B. So, AMD is somehow invoking activity of the
immune system. And, obviously, that last slide gives us some therapeutic targets to consider. Well, I’d like to roll the clock back to 2005
for just a minute. Here are the Mendelian single gene monogenic traits. In 2005, there
were 1,700, and, at that point, vision, ophthalmology had identified about 450 genes that cause
vision problems. In other words, the vision community owned, very strong word, don’t mean
to imply anything, but contributed a quarter of the cloned disease genes, whereas the complex
traits were poking along here, a different scale, at fewer than ten. And then AMD came
on the scene. It was number eight or nine in diseases for which risk genes had been
identified, a rather seminal accomplishment, 2005. Here it is. This was the only gene identified,
only disease gene identified in 2005 for common complex disease. By a year later, 12 months
later, here is a second macular degeneration gene, and here we have a cardiovascular problem,
prolonged QT interval or inflammatory bowel disease, rare company 2006. 2007, medicine
catches up. 2011, oh, my goodness, here’s the state of medicine. This is now, what,
a year and a half ago: 249, 250 medical traits, common complex diseases, 1,600 genetic studies,
the entire genome is populated with knowledge about the diseases you and I see today at
Suburban and at NIH. And — but I don’t want to imply as some people
think I do, I don’t want to imply that life is merely genetic. It’s bad enough to have
the complement factor H gene because that increases your risk of developing AMD fourfold
over not having it, or sixfold for another AMD locus, but if you smoke, watch out. That
fourfold goes to ninefold and this sixfold goes to 22. So, life is complicated, but a
lot of what we deal with is genetic. So, how do we find these genes? The first
three kind of dropped in our lap. A total surprise to me — Emily, thank you for pursuing
this — but how do we find the rest of the genes? The Eye Institute, a few years ago,
under Heman Chin [spelled phonetically], organized a group, a research group, 24 different research
groups, and they pooled their cases, several thousand disease cases. And didn’t schedule
this way, but there was news yesterday that this group, their paper has just been accepted
in Nature Genetics to be coming out soon, which will report a total of 17 loci, 17 genes
conveying risk for AMD. That takes concerted action. And it’s bad enough to remember all those
gene names, but the important thing is those genes begin to cluster. We talked about the
cluster in the complement immune system cascade. Some of the genes cluster in lipoprotein pathways,
others in matrix pathways, others in angiogenesis signaling pathways. So now we’re getting a
flavor of the complexity of AMD. And the Eye Institute is doing the same thing for glaucoma.
Glaucoma has been recalcitrant, no real genes — yes, there are, tigermiocillian [spelled
phonetically] gene, late — what was it? Twenty some years ago. But other than that, genes
have not been found. But getting together a group under auspices
of the National Eye Institute, they just last fall published a whole genome scan, and there
were two loci that popped up. So we hope the genes will be found, but, actually, the lesson
is this is kind of curious. This group met three weeks ago, and what they concluded is
their clinical input is off base. The genetics is fine, but it’s not coming up with things
because the clinicians are saying they really don’t understand the concept of glaucoma.
That’s an admission for our clinicians, right, but it’s an important part of how this field
moves forward, to take genetic information or the lack thereof and have it feed back
into medicine. So, how many genes do we need? Is 17 enough?
There’s a lot of information that just flashed up here, but let me run this real quickly.
If we take those three genes that accounted for about 74 percent of the risk the first
three major genes, it turns out that we classify 74 percent of the true cases, but we would
miss on 31 percent of the controls. Not bad, 2:1. Problem is many, many more people are
in this normal group who will not get AMD. So when you do the multiplication and misclassify
a huge population, misclassify it one-third of the time, it turns out that in seven of
eight people you say are at high risk, you were wrong. That’s not a very good test to
use. So, in fact, you do need a lot of genes, and this is going to be a very complicated
process in complex diseases. Maybe that’s why they’re called complex diseases. I’d like to just wrap this up in a few minutes.
What’s next? Here are some seminal events in medicine. Polio vaccine; many in the room
are old enough to remember the excitement that this generated. And then a decade and
a half ago, cloning a mammal. Oh my goodness, the world is going to fall apart. This was
seminal. And a decade ago, the Human Genome Project, Francis and Craig Venter. Seminal
events. I’d like to — they all made well in time and time, but here’s a seminal event
for ophthalmology, published Nature a year and a half ago. This, folks, is a mouse eyeball
grown in culture from single mouse embryonic stem cells. This is a seminal event. Yoshiki
Sasai did this work. We had him speaking across the street last year. He started with mouse
embryonic stem cells and they grew into not a monolayer of cells, but, in fact, organized
a whole organ, the eye. All that’s missing is the lens, and this thing could see, the
eye could see, but how do you connect it to the brain? Well, we’ve got to figure that
out, and when that’s figured out, we will be able to grow new eyeballs for people. Now
that’s a bold idea. A year ago I took that idea to the National
Advisor Eye Council, the oversight body for the NEI, and said, “Let’s consider being bold.
Let’s consider being audacious.” The Eye Council took that up, and they came up with the term
“Audacious Goals Challenge.” This was an aspirational slide a year ago, but it’s now a reality because
two weeks from, a week from Sunday, two weeks from Sunday at the Bolger Center in Potomac,
we will have 200 people comprising all of these disciplines together to think about
how to stimulate innovative, visionary thinking to take vision forward. So, stay tuned please, because this will be
— two weeks from now; obviously, it takes a little time, but I am pleased, actually,
that a mere 12 months after proposing the idea, in fact, we’re able to act on it with
200 clever-thinking, innovative scientists getting together to envision the opportunities
again. We’d like to be at the edge of current technologies or maybe even beyond where we
are. Ten years to make things play out would be our goal, and that’s a long time. I don’t
want to do science fiction. So let’s stay in the ball park, but let’s actually think
about what we can imagine doing. Can we connect an eyeball grown in a dish into the brain?
I have no idea. But if one could, what would be the implications of that kind of thinking?
So, the Eye Institute will invest a significant part of its resource, our resource, your resource,
because it’s tax dollars, into thinking the next decade and two decades ahead. Well, that’s it. I thank you for your interest.
And I think that we are moving ahead, and I think all of medicine is just leaping forward
now. This started — one measure is a decade ago with Francis and others working on that
human genome. It has proven to be seminal for medicine for research, and now for patient
care. Thank you. [applause] Male Speaker:
[inaudible] comments or questions about [inaudible] — Male Speaker:
The replacement of the genes, is it a one-shot affair or do you have to have repeated replacement
and is there self-generation [inaudible] — Paul Sieving:
Well, that’s a very interesting question. Male Speaker:
Could you paraphrase it for — Paul Sieving:
That’s an interesting question. So, when you do gene therapy, do you do it one time or
does it take repeated dosing? You can do it one time in most cells, and particularly cells
such as the pigment epithelium that don’t divide and replicate. The gene goes in, snuggles
next to the chromosome, the genetic elements that are in the cell naturally, and then acts
as though it had been there a long time, and it stays there. That is certainly the case
so far for the dogs that were treated. Our representative to Congress just died a decade
after the therapy, and had not lost anything that he had recovered. So it looks like it’s
a one-shot deal. And actually, buried in that, is a seminal problem for the pharmaceutical
industry. How do you price it? How do you cure somebody? One shot, how do you price
that one shot? Male Speaker:
Is there a special place that the central nervous system has a sanctuary away from some
of the immune system help [spelled phonetically] in this matter? Paul Sieving:
We think so. The neural tissue, the retina tissue at the back of the eye is relatively
protected from immune attack, but it’s not actually totally isolated. It is simply — the
immune system is slower to act with. So we’re not totally immune, but it does give us a
head start. Male Speaker:
Other comments or questions on it? Male Speaker:
The viruses that are used at vectors, did it cause any problem at all with the lentivirus
or some other virus — Paul Sieving:
Oh, you just snuck that in on me. So do the viruses cause the problem? I thought you were
first talking about what’s used currently, AAV, adeno-associated virus. It seems — AAV
seems not to cause a problem. Lenti is of greater concern. It’s part of the HIV/AIDS
axis, and so those lentiviruses are engineered quite specially and specifically to remove
elements that might cause cellular proliferation, tumor growth, et cetera. So far with the lentiviruses
that have been put in to the human body, they, therapeutically, they are not causing a problem.
I’m sure at some point there will be something that happens, but, in general, I think it’s
a safe statement that prudence, medical prudence, research prudence can overcome the problem. Male Speaker:
Turning that around, do viruses — the origin of diseases [inaudible] viruses? Paul Sieving:
I’m not a virologist. I would look to Bob Nussenblatt sitting back there quietly, who
knows a lot more in answer to your question. In this case, the viruses that are being used,
the genome of the virus codes for some very specific elements, and those elements have
been taken out, reengineered, and put back together, so these viruses are disabled. Male Speaker:
No, I understand that, but historically. Paul Sieving:
Historically, do they cause — well, they can. There are examples of genes in the wrong
place, or genes from one organism, one species in another species, and it is thought that
they were deposited by a naturally occurring viral vector. So, in fact, viruses, genetically,
can cause mischief. Male Speaker:
Yes. Female Speaker:
Yeah, is the genetic and phenotypic data being made publically available so that other investigators
can use it? Paul Sieving:
Absolutely, that’s the point of it. I would encourage you to go to eyeGENE, and you can
read a little bit about it, but this is a public database, public in the sense that
through research permissions, one gains access to it. One gains access to securely coded
information. There’s no private information, individual information, but one can and research
can drill down to that individual level because of the consents that are in place. Kathy Camp:
Hi, I’m Kathy Camp from NIH’s Office of Dietary Supplements. I wonder if you could comment
on the proliferation of direct consumer genetic tests that are now attempting or stating that
they are identifying risks for AMD, given the number of polymorphisms that are now available
to be tested for. Paul Sieving:
So what about commercial gene testing; specifically, the question is phrased for common complex
diseases and for AMD. Again, go to Google, type in AMD gene testing, and I’m sure you’ll
come up with a bunch of commercial sites. What do you make of them? Talk to Kerry next
to you. She’ll have the answers. But here’s my answer. I showed you the example of the
mischief that is caused by imprecise information. The genetic testing that is being done by
these services does not — knows nothing more than we do, and, consequently, they are going
to be mislabeling a considerable number of individuals who will not be getting AMD, but
think they may because the testing is imprecise. So it’s a risky area, difficult area. Male Speaker:
Could you comment on the process of getting this wonderful science into the hands of practicing
clinicians who are out there slugging it out every day? How is that working in the eye
world? Paul Sieving:
How is it working in the eye world to engage day-to-day practitioners? I am pleased to
be an ophthalmologist because I think the ophthalmology community is the best. Boy,
I shouldn’t say that, but it’s very good, and ophthalmologists seem to be curious people,
people who are curious, and they are incorporating genetic information as rapidly as all of medicine
is. Now, one of our strategies with the eye gene genetic testing, in fact, was to engage
community ophthalmologists, and as that map of the United States all coded green except
for six states. The practice community, in fact, is participating in this, and the American
Academy of Ophthalmology meeting every year like all professional societies has specific
sessions on genetics, testing, and implications for practice. Male Speaker:
Do you focus on common disease, or basic knowledge, or both? It seems to me that [inaudible] doctors
understand how to function with this, you know, rather than knowing which exome? Paul Sieving:
That is a critical, critical issue, and, again, I’m going to point to Kerry, because she thinks
about this, as does her compatriot next door, in how does one use genetic information? How
do you — so you’re a practicing physician. You’re seeing a patient with Stargardt. What
do you do with the information when it comes back? It is going to be necessary for all
of medicine to be teaching genetics, hard core genetic knowledge in our medical schools
as they are doing. Male Speaker:
Other comments or questions? Yes. Female Speaker:
For the single gene mutation [inaudible] you just talked about, how can you — how to determine
the location of the [inaudible]? I mean, it could be — involve the whole eyeballs, and
where [inaudible] — Paul Sieving:
So, how do you tailor therapy to the cells and parts of tissues that are in particular
need? Well, for the RPE65, the congenital blindness, leber congenital blindness, RPE65
LCA disease, that is an enzyme deficiency in the retinal pigment epithelium. So you
put the vector right next to the pigment epithelium. You flow the fluid right on to the pigment
epithelium in the operating room, right here when retinal surgery is done. So you can get
the gene in physical proximity to the tissue. Let’s say that there’s an extra ocular muscle
problem. It is easy to put a needle to the muscle, deposit some fluid, and have it suffused
through the muscle fiber. So, in fact, for ophthalmology for the eye as an organ system,
the eye is very amenable to genetic intervention, I would think. Male Speaker:
Other comments or questions? Please join me in thanking Dr. Sieving for a wonderful [inaudible]. [applause]

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