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Gene Therapy, New Drug Battle a Rare But Deadly Disease in Kids

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WEDNESDAY, Nov. 1, 2017 (HealthDay News) -- Babies born with a previously untreatable degenerative nerve disease now have two fresh sources of hope for their future.

Two innovative new therapies for spinal muscular atrophy (SMA) type 1 have proven highly effective in clinical trials, researchers report.

Babies with SMA are born without the gene that promotes production of survival motor neuron (SMN) protein. Without this protein, nerve cells in the spinal cord and brain stem stop working and start to die off.

These babies slowly lose the ability to move their arms and legs. Those with the most severe form, SMA type 1, eventually lose the ability to breathe on their own and rarely survive beyond 2 years of age.

Two research groups say they've produced breakthrough therapies for these children.

First, a new genetic treatment employed a DNA-loaded virus to replace the missing SMN1 gene with a fresh, healthy copy of the gene.

Second, an already-approved drug called nusinersen (Spinraza) was used to promote production of the crucial nerve protein by a backup gene called SMN2.

Both approaches increased survival in babies with SMA and preserved or improved their motor function, the researchers said.

"These are the first realistic treatment options for SMA," said Dr. Ans van der Ploeg. She is chair of the Center for Lysosomal and Metabolic Diseases at Erasmus MC University in Rotterdam, the Netherlands.

Both therapies aim to increase production of SMN protein in the motor neurons and thereby improve the survival and function of motor neurons, she said. This leads to better muscle and respiratory function and survival, added van der Ploeg, who wrote an editorial accompanying the two clinical trial reports.

About one in every 11,000 babies is born with SMA, and six in 10 of them have type 1, said Dr. Richard Finkel. He is chief of neurology at Nemours Children's Hospital in Orlando, Fla., and lead researcher of the nusinersen clinical trial.

The gene therapy treatment was tested in 15 babies with SMA type 1. All received one intravenous dose of a genetically engineered virus containing the new copy of the SMN gene. The virus is named AVXS-101. This was a phase 1 trial to test safety.

"We are trying to replace SMN1 with enough gene that works in enough nerve cells to change function," said lead researcher Dr. Jerry Mendell, director of neuromuscular disorders and neurosciences at Nationwide Children's Hospital in Columbus, Ohio.

All 15 patients treated with AVXS-101 are still alive, Mendell said, and some are thriving. Higher doses produced better responses.

"All the patients in the trial have improved with the exception of one," Mendell said. "We have patients living out past three years now. And we had patients who actually could walk and run and play."

Nusinersen was tested in 80 babies at 31 hospitals as part of a phase III trial prior to its 2016 approval.

"The drug is kind of novel," Finkel said. "It's not your standard off-the-shelf pharmacy kind of drug. It's similar to a little piece of DNA."

The drug targets the SMN2 gene, a backup gene to the SMN1 gene missing in these babies. It is injected into the spinal fluid. Patients undergo four "loading doses" via lumbar punctures within the first two months, and receive maintenance doses every four months, Finkel said.

Nusinersen amps up protein production by the SMN2 gene, potentially halting progression of nerve damage.

In the trial, 41 percent of infants who received the earliest treatment with nusinersen and 51 percent of infants in the final analysis experienced stable or improved motor function, the researchers reported.

Babies treated with nusinersen also were more likely to survive. The risk of death was 63 percent lower in the nusinersen group compared with the control group, the findings showed.

Results were so promising that the clinical trial was halted early so the control group could receive nusinersen, the study authors said.

"This study shows the drug has a clinically meaningful response with a higher likelihood of improved survival and motor function," Finkel said.

Nusinersen, made by Biogen, is available for treatment now.

AVXS-101 will proceed to broader clinical trials involving more children at multiple hospitals, Mendell said.

Neither treatment had any clinically significant side effects, according to the researchers. The treatments do not constitute a full cure for children who have already developed symptoms of SMA. However, both research teams hope that kids treated before symptoms arise won't suffer any degenerative nerve loss.

Finkel said, "If we can get these babies before they show these signs of weakness, I think that's going to give the best chance for the most robust response, possibly even a cure."

Van der Ploeg added that younger, less severely affected patients had a better chance of a good response in the trials. Also, while the gene therapy pilot trial results are promising, more data are required, she noted.

The nusinersen trial was paid for by Biogen and the drug's developer, Ionis Pharmaceuticals. The AVXS-101 trial received funding from AveXis, developer of the designer virus.

Results of the studies were published in the Nov. 2 issue of the New England Journal of Medicine.

More information

For more on spinal muscular atrophy, visit the Nemours Foundation.

SOURCES: Ans van der Ploeg, M.D., Ph.D., chair, Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Richard Finkel, M.D., chief, neurology, Nemours Children's Hospital, Orlando, Fla.; Jerry Mendell, M.D., director, neuromuscular disorders and neurosciences, Nationwide Children's Hospital, Columbus, Ohio; Nov. 2, 2017, New England Journal of Medicine
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