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Gene therapy can be defined as the
introduction of new genetic material into a living cell or organism for
therapeutic purposes. Traditionally, we administer medication to
patients in order to achieve a therapeutic response. Gene therapy, on
the other hand, is a novel approach in that it allows a patient to
“manufacture” its own treatment.
Before gene therapy can be applied to cats, the feline genome must be
mapped. Recently, the University of Missouri selected a cat that will
serve as the genetic model for all cats in the feline genome project.
The cat, named Cinnamon, is the offspring of two Swedish purebred
Abyssinian cats. Cinnamon has a long and well-documented pedigree. The
cat’s blood will be used to map the feline genetic structure, allowing
for each gene’s function to be studied in detail. “I’m extremely
enthusiastic about the cat genome being sequenced”, says Kristina
Narfstrom DVM, PhD, endowed professor of University of Missouri’s
veterinary school. “This will simplify the search for specific gene
defects causing various forms of hereditary disease in cats”. Once it is
determined which genes are responsible for specific diseases in the cat,
such as blindness or cancer, affected cats and carrier cats can be
detected in the cat population by performing simple blood or tissue
tests. “Knowledge of specific gene defects may give rise to the next,
very exciting step, that of treatment” says Dr. Narfstrom.
Cats are an excellent animal model for human genetic diseases because
their genetic makeup has remained fairly consistent over time. Cats, as
a species, haven’t had the extensive crossbreeding that dogs have had
over the centuries. In fact, scientists believe that the canine genome
has been scrambled at least fourfold, as humans have deliberately
modified canine behavior for uses such as herding or hunting. This is
not so for cats. In fact, cats have the most highly conserved gene order
of all mammals. The consistent makeup over the ages simplifies the job
of sequencing the genome.
Gene therapy is a relatively new science. In 1990, the first two
approved gene therapy trials were performed in the United States. Though
both trials were unsuccessful, it started a wave of research and
clinical trials. In 1999, the death of a young patient that was being
treated for a liver enzyme deficiency was a major setback however, just
one year later, the first two successful clinical trials using gene
therapy were reported – one for SCID (severe combined immunodeficiency,
a.k.a. the “bubble boy” syndrome) and the other for hemophilia B. Since
then, there have been hundreds of clinical trials, most focusing on
cancer research. In veterinary medicine, only a few successful gene
therapy trials have been reported. For example: treatment of hemophilia
B in five dogs, restoration of vision in three briards with a hereditary
retinal disorder, and disease regression and prolonged survival in 12
dogs with malignant melanoma. In cats, gene therapy has been used to
treat genetic conditions such as mucopolysaccharidosis and lipoprotein
lipase deficiency. “Hereditary diseases of the eye are especially
amenable for gene therapy”, says Dr. Narfstrom. “I have treated a
retinal disease of dogs that have been blind since birth by using
corrective gene therapy. My plan is to also perform corrective therapy
in Abyssinian cats when the gene defect for PRA (progressive retinal
atrophy) has been elucidated”.
Genes can be transferred either by introducing them directly into a
patient’s cells (for example, injecting into a tumor), or by removing
cells from a patient (such as bone marrow), introducing the gene, and
then returning the cells back to the patient. For the gene to be
transferred successfully into the patient’s cells, a vector (an agent or
carrier) is required. Most gene therapy clinical trials have used
viruses as vectors for gene transfer. Viruses are ideal vectors because
they’re skillful at entering cells, traveling to the cell’s nucleus, and
“hijacking” the cell’s genetic material so it can make more copies of
its own genes. Viral vectors are currently the most efficient means of
transferring genetic material into a cell.
One potential application of gene therapy that is currently being
investigated is the use of viral vectors to deliver the erythropoietin
gene to cats. Erythropoietin is a hormone, produced by the kidney, that
instructs the bone marrow to produce red blood cells. Often, when cats
are in kidney failure, their damaged kidneys produce an inadequate
amount of this hormone. As a result, many cats with kidney failure
become anemic. The anemia leads to weakness, lethargy, and poor
appetite. The anemia can be treated with injections of human
erythropoietin, however, in a significant number of cats, their immune
systems recognize this protein as being foreign, and they make
antibodies against it, rendering the erythropoietin ineffective. In
addition, these antibodies cross-recognize the cat’s own erythropoietin
and neutralizes it as well. When this happens, the anemia becomes
immediately life-threatening and a transfusion is necessary to save the
cat’s life. At this point, most cat owners elect euthanasia. By devising
a method of delivering more copies of the feline erythropoietin gene to
cats that are deficient in this hormone, the need for frequent
injections of foreign protein can be avoided. The erythropoietin gene is
an ideal candidate for gene therapy because the hormone does not have to
be produced at the original site (the kidney). This means that the DNA
can be inserted in a more easily accessible tissue, such as muscle. And
the activity of the inserted gene can be easily monitored: if the gene
is working, the red blood cell count will increase. This can be measured
easily and inexpensively.
Despite the promise of gene therapy, concerns about safety and efficacy
remain, as relatively little is known about the durability of the
transferred genes, and the practicality of repeated gene therapy
treatments. There are also ethical considerations. Although there have
been few clinically applicable treatments thus far, once the feline
genome is completely mapped, the potential for treatment of inherited
and acquired genetic disorders is limitless.
Updated 2/9/06 |
