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The animals lived longer and showed milder symptoms than untreated mice, although they didn't survive as long as wild type mice. 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) gene—which causes SMA in humans—in 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. SMN1 encodes 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 fetus’s 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 Children’s 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....
Published in Molecular Therapy (August 31, 2019):
