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.