The New
Frontier is Coming: Genetic Testing,
Pharmacogenetics, and Gene Therapy
Douglas J. Rhee, M.D.
Fictional Case Scenario of the (not so distant)
Future
Mr.
Smith goes to the ophthalmologist a few days after his 20th
birthday to be checked for glasses because he is having trouble
seeing the blackboard in lecture.
Along with his initial ophthalmologic exam, he consents
to have a standard glaucoma genetic screening panel since there
is a family history of vision loss from glaucoma. It is discovered that he has a mutation in gene X which is associated with a 90%
penetrance of disease; additional
factors indicate that if he were to develop glaucoma, it would
be moderately aggressive (i.e. Genetic
Testing). His SNP and
allelic screening indicates that he has a high likelihood of a
poor response to carbonic anhydrase
inhibitors and alpha agonists but an excellent response to beta
blockers and PG analogues. It also reveals a tendency to a topic reaction
to benzalkonium chloride (i.e. Pharmacogenetics).
During
his clinical exam, he has an elevated intraocular pressure of
30 mmHg, with normal corneal thickness, open angles, and enlarged
optic nerve cups of 0.7 OU. A baseline visual field shows no abnormality
while optic nerve topography and OCT reveal measurements
to be on the borderline of the age adjusted normograms. He is scheduled for gene X replacement in the trabecular meshwork (i.e. Gene Therapy). If too much damage in the trabecular meshwork
has already occurred, resulting in only a modest lowering of his
IOP, then he will be placed on a neuroprotective
agent, and options for initial IOP lowering therapies such as
medications, laser trabeculoplasty, or modified glaucoma filtering surgery will
be discussed. He is reassured
that with “modern” glaucoma management, new epidemiologic studies
indicate his probability of going blind from glaucoma is less
than 1 percent.
Genetic
Testing: Testing a patient’s genetic make-up from a representative
tissue (blood, buccal mucosal swab,
potentially hair) to screen for the presence of mutations, allelic
differences, or single nucleotide polymorphisms which have been
shown through epidemiologic studies to correlate with clinically
relevant outcomes.
Basic Definitions:
Single
Nucleotide Polymorphism (SNP):
A change in the DNA code of a gene of one base pair that
does not alter the function of the gene product in any way.
Allele: A change in the DNA code that alters, but not
destroys the function of the gene product.
An example is eye color in Drosophelia melongaster.
Mutation: A change in the DNA code of a gene that destroys
the function of the gene product.
Pharmacogenetics: Use of SNP screening and/or allelic differences
to predict outcomes of medication use.
Gene Therapy:
Gene
therapy can have two different meaning:
1) To insert a healthy copy of
a defective gene or 2) to insert a normal human gene into a target
tissue to improve the function of that tissue
Now Not So Fictional Case
Mr.
Smith goes to the ophthalmologist a few days after his 20th
birthday to be checked for glasses because he is having trouble
seeing the blackboard in lecture.
Along with his initial ophthalmologic exam, he consents
to have a standard glaucoma genetic screening panel since there
is a family history of vision loss from glaucoma. It is discovered that he has a mutation in TIGR/myocilin
which is associated with a 90% penetrance
of disease; presence of
the mt1 polymorphism in the promoter region of myocilin
indicates that if he were to develop glaucoma, it would be moderately
aggressive (i.e. Genetic Testing). His SNP and allelic screening indicates that
he has a high likelihood of a poor response to carbonic anhydrase
inhibitors and alpha agonists but an excellent response to beta
blockers and PG analogues. It
also reveals a tendency to a topic reaction to benzalkonium
chloride (i.e. Pharmacogenetics).
During
his clinical exam, he has an elevated intraocular pressure of
30 mmHg, with normal corneal thickness, open angles, and enlarged
optic nerve cups of 0.7 OU. A baseline visual field shows no abnormality
while optic nerve topography and OCT reveal measurements to be
on the borderline of the age adjusted normograms. He is scheduled for gene X replacement in the trabecular meshwork (i.e. Gene Therapy). If too much damage in the trabecular meshwork
has already occurred, resulting in only a modest lowering of his
IOP, then he will be placed on a neuroprotective
agent, and options for initial IOP lowering therapies such as
medications, selective laser trabeculoplasty, or trab with anti-TGFb2
will be discussed. He
is reassured that with “modern” glaucoma management, new epidemiologic
studies indicate his probability of going blind from glaucoma
is less than 1 percent.
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