New research indicates that gene therapy treatments delivered via amniotic fluid injection could improve treatment outcomes of spinal muscular atrophy (SMA).
A paper published in May in Science Translational Medicine, co-authored by Charlotte Sumner, professor of neurology, neuroscience and genetic medicine at the Johns Hopkins University School of Medicine, finds that prenatal amniotic injections of these therapies, known as antisense oligonucleotides (ASOs), improves outcomes in two mouse models of severe SMA.
Furthermore, ASOs delivered in this manner showed broad distribution to the brain and spinal cord of fetal lambs, which are similar to humans in their fetal physiology. ASOs are a class of gene therapies that bind to and change messenger RNAs to alter their processing.
The implications are vast, says Sumner, both for treatment of SMA and for other neurologic diseases with onset before or at birth.
“There is significant interest in determining how we might utilize emerging genetic therapies in utero because there are many very severe diseases that start very, very early,” she says. “This work really opens up the idea that you can use ASOs for SMA, but also for lots of other disease indications with in utero onset.”
SMA is a motor neuron disease affecting about one birth out of 10,000. It’s caused by recessive loss-of-function mutations of a gene known as SMN1, resulting in a deficiency in survival motor neuron (SMN) protein. Patients retain one or more copies of the SMN2 gene, but it is alternatively spliced, reducing its ability to make full-length functional SMN protein but also making the gene a candidate for ASO treatments that can repair the splicing mechanism.
Babies born with SMA experience rapid degeneration of the motor neurons, which extend their axons from the spinal cord to their muscles. This causes severe muscle weakness. Before treatments became available, infants with severe SMA typically did not live beyond the age of 2.
Between 2016 and 2020, the Food and Drug Administration approved three genetic therapies, which each increase SMN, all with similar efficacies in clinical trials. “Remarkable benefits can occur when these drugs are given before symptom onset,” Sumner says. “Babies who would never roll over, never achieve head control, never sit, now can reach these motor milestones.”
In many countries, including the U.S., babies are screened for SMA at birth, so treatments can start quickly. “It seems that days and weeks can make a substantial difference in disease outcomes,” Sumner says. “In the case of babies with severe SMA, even when treated neonatally, many continue to have significant neurological deficits. Based on what we have learned regarding the importance of treatment timing, it is likely that in utero treatment would result in further benefit. However, can genetic therapies be safely and effectively delivered in utero?”
A few studies had evaluated ASOs for in utero use in other disease indications, Sumner says, but they have not been examined in SMA and never in large animals. “This is the first comprehensive study examining splice-switching ASOs targeting the SMN2 mRNA, showing their efficacy in SMA mouse models and their biodistribution in a large animal model.”
A key challenge is how to safely administer ASOs in utero. “The work of this paper was to ask if we can safely and effectively administer ASOs in utero,” she says. “ASOs are exploding as a category of new medicines that we can probably use in multiple disease indications, but we don’t really know how best to deliver ASOs in utero.
“We found that by injecting ASOs once into the amniotic fluid in both small and large animal models, we could see that the fetus could swallow it and then it would distribute to brain and spinal cord, likely because the blood-brain barrier is immature at this time in development. In mouse models with SMA disease features, we improved outcomes above those seen when we gave the drug only postnatally.”
The next step, she says, is finding the right ASO for a clinical trial. The ASO currently used for patients with SMA was approved nearly 10 years ago. “We would envision that a new-generation ASO would be more appropriate for testing in utero,” she says.
Importantly, another strategy for treating SMA in utero is also being explored. In 2021, Sumner and others published a paper, also in Science Translational Medicine, showing that one of the other FDA-approved gene therapies, a small molecule that modulates SMN2 splicing to produce more SMN protein, can be administered to pregnant mice, cross the placenta and reach the SMA fetus to improve disease outcomes.
Subsequently, a study reported successful in-utero treatment of a fetus with severe SMA, who showed no evidence of SMA at 2 years old. Other cases have been treated “off label” in this way, including one at Johns Hopkins. This early experience is promising, but the sample size is small, and further research is needed to confirm the safety and efficacy of this strategy, Sumner says.
The potential appears to be enormous, she says: “Although still in its infancy, fetal genetic medicine could be a new frontier that evolves rapidly over the coming years.”