Genetics and Glaucoma
Chat Highlights
December 17, 2003
Norma Devine, Editor
On Wednesday, December 17, 2003, Dr.
George Spaeth, a glaucoma specialist at Wills, and the
glaucoma chat group discussed "Genetics and Glaucoma."
Moderator: Welcome
back, Dr. Spaeth. During our last chat on genetics we learned
that genetic causes for glaucoma have been known for years, but
only by observing families. Now actual molecular biologic
defects are being identified, and some can be changed. How
is it possible to change the defects, and can some glaucomas be
cured by changing a molecular defect?
Dr. George Spaeth: Not
yet, but some day. The body works by proteins (often enzymes)
stimulating or suppressing actions. Thus, eye fluid runs
out of the eye at a rate that is affected by how the proteins
in the eye affect the drainage apparatus. Now, if we can
make those proteins start acting or stop acting, then we can affect
the amount of fluid that runs out (or runs in). Doug Rhee,
in our department here, is working on one of those proteins now.
The challenge is to find a way to affect just that protein.
P: How might that be
done?
Dr. George Spaeth: One
way that it can be done is by sending a new gene into the eye
to replace or substitute for one that is already there.
This can be done by attaching the gene to a virus that will infect
the cell that houses the gene you want changed. So, we can
put this new healthy gene on a virus, like the virus that causes
colds, and that virus is the means to get the gene onto the cells.
In other words, the gene gets attached to the cold virus and the
virus then infects the body and transfers ("transfects") the gene
into the body. The problem is that you have to make sure the gene
gets onto the cell you want. Genes already there can
be "upregulated" or "downregulated" by drugs, hormones, etc.
P: In the earlier chat,
it was mentioned that glaucoma genes are strongly deterministic
for actually getting the disease. But how are the genes
expressed? Are they predisposed to expression if there
are increased risk factors [such as high intraocular pressure
(IOP) or vascular dysfunction] or are they directly neuropathic,
predispose to expression in a less vital optic nerve that's less
capable of withstanding injury?
Dr. George Spaeth: All
of the above and none of the above. There are many, many
genes involved in the development of glaucoma. In some cases,
the gene is very powerful, such as the gene that is associated
with glaucoma in young adults. Here you may need nothing
more than that one gene to cause high IOP. That type of
glaucoma is always associated with high IOP.
P: Last year, Drs.
Polansky, Juster and you submitted for publication a manuscript
entitled "Association of the Myocilin MT.1 Promoter Variant with
the Worsening of Glaucomatous Disease over Time." Has there
been any further demonstration that "a genetic marker can independently
identify individuals with primary open-angle glaucoma who are
likely to deteriorate in comparison to those who are less likely
to deteriorate?"
Dr. George Spaeth: No.
That is a difficult study to replicate, because it takes
lots of patients who have been followed for many years.
It takes about ten years for glaucoma damage to be severe enough
to distinguish those who will get worse from those who won't.
P: Is gene replacement
a new procedure? Is it in clinical trials?
Dr. George Spaeth: No
actual clinical trials have been conducted in human beings.
But there are lots of animal experiments in which the genes are
made more or less active and some in which new genes have been
placed in animals.
P: Could altering genes
possibly cause unwanted or unanticipated results?
Dr. George Spaeth: Yes.
One of the biggest problems is specificity. How can you
be sure the gene you add won't work on other systems to cause
unwanted effects? You can't. But as methods of introducing
the genes get better, and the actions of genes are better
understood, that problem can probably be overcome.
P: How do you get the
virus with the gene to go to the eye?
Dr. George Spaeth: You
pick a vector (such as a virus) that is known to infect certain
tissues.
P: Aren't there genetic
links that would be disrupted by genetic therapy? Say, the
drainage in the eye might be linked to something else in the body
that you would not want to disturb.
Dr. George Spaeth: That's
true. For these reasons a great deal of work relates to
the question of what modifies the actions of genes. Many
of our genes don't work all the time. Something has to stimulate
them or turn them on. Thus, one of the challenges is to
find what turns genes on and what turns them off.
P: Have pharmaceuticals
already affected genetic manipulation?
Dr. George Spaeth: Yes.
And the field of pharmacogenetics is a hot one. Thus, if
we knew that drug X worked in a person with gene Y but not gene
Z, then we would know to use drug X in a person with this genetic
make-up.
P: Could gene therapy
work with someone who has had congenital glaucoma for 20 years
and several eye operations?
Dr. George Spaeth: Once
structural damage has occurred, it is not likely to be reversed.
So, in terms of making that person better, the answer is no.
But that person may have problems with the amount of fluid entering
the eye. Genetic modification could possibly reduce the
amount of fluid made and so lower the IOP.
P: You mentioned that
certain hormones can "regulate" some genetic activity. Well,
the body produces hormones, so is it known whether the body itself
can regulate genetically scripted activity?
Dr. George Spaeth: Yes.
Steroid hormones (cortisone and the like) are potent modifiers
of gene action. In fact, the most important gene linked
to glaucoma was studied because steroid drops make the IOP rise
in some people in a way that is familial, that is, genetic.
P: Is it overly simplistic
to assume that since regulating genes with drugs and hormones
is less difficult to achieve than, say, gene splicing, we may
expect to see that regulation earliest in clinical practice?
Dr. George Spaeth: Regulation
of genes is probably easier and more reversible.
P: Would you say that
gene splicing is the leading edge of glaucoma therapy and likely
the most productive?
Dr. George Spaeth: The
leading edge? Yes. The most productive? No.
It will probably be a long time, if ever, before "gene splicing"
really works.
P: Correct me if I'm
mistaken, but I thought every cell in the body had the same amount
of DNA. So, if you're going to genetically manipulate the
eye, what happens to the genetic coding in the other body cells
of a person?
Dr. George Spaeth: Cells
are different because the DNA is not expressed the same way in
different cells. For example, liver cells have different
chemical actions in them than muscle cells.
P: When would you estimate
we would actually see benefits from current genetic research?
Dr. George Spaeth: In
terms of modifying cell behavior -- that is, the ways the genes
express themselves -- we are there now. In terms of gene
splicing, it will be years and years for human beings.
P: This may sound a little odd, but
if naturally occurring steroid hormones can modify gene action,
can't the mind, the psyche, under stress do likewise?
Dr. George Spaeth: NOT
odd, but right on target. Stress can affect blood pressure
and eye pressure, too. The mind can affect health in many
ways, including susceptibility to infection.
P: I participated in
a gene research study out of Boston years ago with family members.
You don't happen to recall it do you? I'm the only one in
my family, except for a cousin, who has glaucoma.
Dr. George Spaeth: Joe
Janey Wiggs in Boston has done literally hundred of genetic studies.
Moderator: Dr. Spaeth,
thank you very much for participating in the last chat of the
year. Happy holidays and please come back in 2004.
End of highlights for December 17, 2003.
On January 7, Dr. Wilson discussed "Pseudoexfolition Glaucoma"
in the Chat room. Click here for highlights
of that meeting.
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