Karen Weintraub Contributor GEN
Gene Therapy Approach Pays Off for Babies Who Would Otherwise Have Died
Over the course of his career, Tom Crawford, M.D. has held 70 babies he knew would miss every major milestone. They would never roll over, walk, or speak their first word. They would die before reaching the age when their healthy peers were outgrowing diapers.
Now Dr. Crawford, a neurologist at Johns Hopkins University Medical Center, is pretty certain he’ll never have to tell another family that their child is destined for the same fate.
Two new treatments for spinal muscular atrophy (SMA), the neurodegenerative disease he has dedicated his career to addressing, have completely altered the treatment landscape.
“It’s like the elimination of polio,” he says, though, like other medical professionals, he stops short of calling either of the new therapies a “cure.”
Two papers and an editorial in the current issue of the New England Journal of Medicine outline the two different approaches to treating the worst form of SMA. One of the therapies, generically called nusinersen and marketed as Spinraza by Ionis Pharmaceuticals and Biogen Inc., was approved by the FDA in late 2016. Spinraza alters RNA, the genetic messenger responsible for translating the genetic code into proteins that carry out cells’ various functions.
The second treatment, which is at an earlier stage of research, is a gene replacement therapy meant as a one-time treatment to add back the missing SMN1 gene that makes a protein of the same name.
Without that protein—which Spinraza generates a different way—the brain can’t send messages to the motor neurons that link it to muscles, and the nerves and muscles atrophy. Patients with SMA produce very little SMN protein. The severity of the disease is linked to some genetic differences that influence the amount of protein produced.
Both therapies seem to be equally effective at getting patients’ bodies to produce the SMN protein, though each approach has its strengths and weaknesses, according to Jill Jarecki, Ph.D., who is chief scientific officer at Cure SMA, an advocacy group. FDA-approved Spinraza is further along the research pipeline, but it must be delivered via a spinal tap four times a year; the investigational gene therapy, which is being marketed by AveXis Inc., of Bannockburn, IL, offers the promise of a one-and-done treatment, she says.
“We believe there’s a need for multiple different approaches,” Dr. Jarecki says, adding that there are also two oral drugs being developed to treat SMA, one by Roche and the other by Novartis.
All the activity makes this is an incredibly exciting time for the SMA field, but she doesn’t want to raise false hopes, or neglect the 8,000–10,000 American children who are too old to benefit from these new therapies.
The new study of Spinraza, led by Richard Finkel, M.D., of Nemours Children’s Hospital in Orlando, FL, found that the earlier a child with SMA gets adequate amounts of SMN protein, the better off he or she will be. This makes sense, because motor neurons cannot be resurrected or grow back, so more damage suffered prior to treatment translates into worse symptoms later on.
To ensure that no one will ever be too old for effective therapy again, doctors, drug companies, patient advocates and families are now pushing to add SMA to the list of diseases screened for at birth. Such a screen was never necessary before there was treatment, but now it has taken on tremendous urgency, says Dr. Crawford, who was not involved in either paper, but who has been involved in other trials of the Spinraza therapy and is now recruiting participants for a new trial of the gene therapy.
The gene therapy, called AVXS-101, uses a virus to infect virtually every cell in the body and adds a working copy of the SMN1 gene. This new gene sits inside the cells, but does not incorporate into the child’s DNA; it’s essentially a supplemental gene, according to Jerry Mendell, M.D., who led the research at Nationwide Children’s Hospital in Columbus, OH, where the gene therapy was developed.
All 15 children in the gene therapy trial were alive at 20 months and didn’t require ventilation. Only 8% of untreated children with the most severe form of SMA typically escape ventilation by that age.
The first three babies in the study received a dose of the gene therapy that was considered safe. But they saw only modest improvements.
The other 12 babies received a higher dose and saw substantial change from the normal disease course. All 12 can now sit, and 9 can sit for more than 30 seconds without assistance—a milestone never reached by any untreated SMA type 1 babies. Two have learned to walk, and all continue to improve, Mendell says.
The virus caused only one minor side effect—temporary inflammation in the liver—which is easily treated with steroids, Mendell says. One infant was turned away from the trial because he or she had already had been exposed to the adeno-associated viral vector used to deliver the gene therapy, and had developed antibodies to it. The virus was combined with a hybrid cytomegalovirus enhancer–chicken beta-actin promoter.
It is not clear if the single dose of gene therapy will last forever, but so far, the signs are good. The first babies in the trial are still producing SMN three years after their treatment, Mendell says, and hemophilia patients treated with gene therapy have an even longer track record.
“There are always challenges in research and we’ll have to meet the challenges,” he says. “We’re preparing for every possibility.”
One of the big issues with both therapies is their cost. Spinraza is priced at $750,000 for the first year, when extra priming doses are needed, and $325,000 for each year after that — apparently for the child’s entire life.
No price has yet been set for the gene therapy, but it’s expected to reflect its benefit and the comparison with Spinraza.
Both treatments are “pretty close to a cure,” but not quite, Dr. Crawford says. Some damage from SMA may occur even before birth, and, he adds, “we’re not going to make people in motorized wheelchairs get up and start running.”
Still, the progress has been remarkable.
“I started out with this being the worst, most hopeless disease there was,” notes Dr. Crawford, but luck has repeatedly been on the side of researchers and families. “Things have really broken our way more than a couple of times.”
*This story was updated on 11/2/17.
Karen Weintraub is a health and science journalist based in Cambridge, MA.