Gene-therapy research has been built on the idea that you
can manipulate a virus — a natural invader — to act as a medical Trojan horse
and carry a replacement gene. There have been notable and deadly failures.
There have been starts powered by promise that fizzled in practice.
This time, the real excitement began to build in 2009 when
the mice in which researchers tested the SMA therapy kept living.
Researchers at Children’s built a gene therapy with SMN1
constructed in the lab. It is designed to hitch a ride within a harmless virus
found naturally in monkeys that also proved to cross the blood-brain barrier
and land within motor neurons.
Rodents created at Ohio State University to model human SMA
patients would die in a couple of weeks with no intervention.
But when researchers at the Children’s Research Institute
infused them with the therapeutic agent shortly after birth, they lived on.
“We had animals that were living past 30 days and 50 days
and the results were looking too good to be true,” said Brian Kaspar, whose lab
became singularly focused on the work.
They’d work late into the night, drive in on Christmas Day
to check on the mice. They were energized and staggered by the results, he
said.
An increasingly skeptical Kaspar even ordered tests on the
rodents to make sure they were SMA mice and that they didn’t mistakenly start
with healthy animals.
“Lo and behold, they were SMA mice. We had them living out
100 days and 200-plus days. We had some that lived past 400 days to the point
where we end the experiment,” he said.
After tests in pigs with SMA, then nonhuman primates to
ensure the therapy crossed the blood-brain barrier in an animal most like a
person, steps toward human research began.
Was it possible, they wondered, that this would hold up in
children?...
Tenley, in December, became one of eight babies who’ve so
far had the one-time, one-hour infusion of experimental gene therapy that
researchers are beginning to let themselves believe might rescue babies from
this disease.
Some had a low-dose infusion, others a dose that Dr. Jerry
Mendell calls “intermediate.” The goal is to find a sweet spot, where you reap
optimal benefit but don’t deliver a deadly dose…
So far, the babies who’ve had the heftier dose have done
significantly better, which was expected. And it appears that delivering the
treatment as early as possible is critical, said Mendell, who directs the
Children’s Center for Gene Therapy.
On a graph that plots their developmental progress over
time, every baby is either not getting worse or is improving. If you looked at
a similar graph of untreated SMA babies, the lines would all go down.
“No one in this trial has succumbed to the disease, which is
really exceptional,” Mendell said, pointing to one baby’s chart. The measures
have hit a normal range.
If the babies continue to do well and the Food and Drug
Administration eventually OKs the treatment for any baby with SMA, routine
testing after birth could find newborns with the disease and prompt immediate
treatment, Mendell said…
Mendell said it’s unlikely that motor neurons already lost
to the disease can be recovered, so speeding the treatment is critical.
After about a year of testing in children (the oldest is
about 18 months now), Mendell cautions that he and his collaborators still have
much to learn about dosage, timing and what happens in the long term.
So far, the most concerning side effect has been liver
trouble, which has proven manageable with medication, Mendell said.
http://www.dispatch.com/content/stories/local/2015/06/17/reaching-for-hope-and-a-cure.html
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