StemCell Therapy

Earlier this year, the US Food and Drug Administration approved the most expensive drug ever to hit the market, a gene therapy for spinal muscular atrophy. SMA is a neuromuscular disorder that, in severe cases, can lead to infant death. The genetic correction is currently used to treat affected newborns, but as symptoms for some types of SMA may appear before birth, an earlier treatment would be potentially more effective.

In a study published December 4 in Molecular Therapy, researchers were able to fix a mutation in the survival motor neuron 1 (SMN1) genewhich causes SMA in humansin mice modelling the disease, while they were still inside their mothers uterus. The treated mice lived longer and had fewer symptoms than untreated animals.

Tippi MacKenzie, a fetal and pediatric surgeon at the University of California, San Francisco, who did not participate in this study, says it is an important paper because it is the first time fetal gene therapy has succeeded in SMA mice. Before you even think about doing something in patients, you have to first do it in the disease model of the mouse . . . so this group has supplied a very important piece to the literature, she adds.

SMN1encodes an essential protein for the maintenance of motor neurons, which are nerve cells in the brain and spinal cord responsible for controlling muscle movement. The result in children with mutations in the gene is the loss of motor neurons, leading to muscle weakness and associated complications. SMA affects one out of every 6,000 to 10,000 babies.

Correcting the SMN1 sequence is a potentially efficient treatment for those born with SMA. Zolgensma, the recently approved medication for this disorder, consists of an intravenous administration of an adeno-associated virus that ferries a functional copy of the SMN1 gene to the brain.

To see if the same fix could be accomplished before birth, the research team tested two different injection methods: one into the placenta (intraplacental or IP) and the other into one of the brain lateral ventricles (intracerebroventricular or ICV). The latter proved to be more effective. By injecting the viral vector into the fetuss brain, the virus will go directly into the cerebrospinal fluid, and it will transduce motor neurons in the spinal cord with a very high efficiency, compared to the IP [injection], says Afrooz Rashnonejad. who participated in this study while working at Ege University in Izmir, Turkey, but has recently moved to Nationwide Childrens Hospital in Columbus, Ohio.

Rashnonejad and her colleagues then monitored the injected mice that were carried to term. Those treated with the vector carrying a functional copy of SMN1 lived a median lifespan of 63 or 105 days (depending on the type of cassette carrying the gene), much longer than untreated SMA mice, which did not survive more than 14 days, but still less than wildtype pups, which had a median lifespan of 405 days. The treated mice were also heavier than untreated mice, but smaller than healthy mice.

The investigators also observed differences at the cellular and molecular levels. SMN protein levels were completely recovered in the brain and spinal cord, and the number of motor neurons was higher in treated animals.

I was just very impressed by what theyve done, says Simon Waddington, a gene therapy researcher at University College London who did not participate in this work, but was one of the reviewers of the paper. He adds that he and other colleagues had previously tried fetal gene therapy on SMA mice, but had failed as it is a technically difficult experiment. So it was really nice to see this group actually did a really good job.

This is the first time viral vectors have been used to successfully boost gene expression in SMA mice before birth. Interventions to edit the genome in utero have been previously used in mice that model other severe genetic diseases. Last year, for instance, Waddington and colleagues used fetal gene therapy to treat mice affected by Gaucher disease, a neurodegenerative disorder that can be fatal for newborns. Other successful attempts include intrauterine gene editing for mice affected by -thalassemia, an inherited blood disorder, and mice suffering a monogenic lung disease that normally results in newborn death.

MacKenzie says that, in a recent national meeting on in utero gene therapy, it was discussed how to move forward with a clinical application to the FDA. We are definitively moving towards that direction, but we dont have a particular application yet, because its still not clear which disease should be the first.

SMA makes a lot of sense because its so severe, MacKenzie adds. But at the same time, the results that are coming out at conferences, she observes, suggest that newborn babies receiving Zolgensma are doing pretty well, better than anybody could have imagined. So its not clear that you have to go before birth. A good candidate, she explains, would be a very rare type of SMA, where the baby dies before birth.

Waddington says that researchers might have to wait for neonatal gene therapy to become standard for certain diseases before using fetal gene therapy in humans. Once we actually understand how efficient this is, and if we come to the point where we discover that the earlier that you go the more effective it is . . . in a human setting, then we may be able to do fetal gene therapy. I think that we are looking at more than five years away before thats even likely to happen, he hypothesizes.

A. Rashnonejad et al., Fetal gene therapy using a single injection of recombinant AAV9 rescued SMA phenotype in mice,Molecular Therapy, 27:212333, 2019.

Alejandra Manjarrez is a freelance science journalist. Email her atalejandra.manjarrezc@gmail.com.

See the article here:
Fetal Gene Therapy Helps Mice with Spinal Muscular Atrophy - The Scientist

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