Liver-targeting gene therapy lowers mice whole-body SMA symptoms
Treated mice lived longer, were better at motor tasks, had fewer liver problems
Gene therapy that selectively delivers the SMN1 gene to the liver reduced alterations related to spinal muscular atrophy (SMA) in a mouse model, restoring muscle size and correcting pancreatic issues.
Mice that received liver-specific SMN1 also lived longer, performed better on motor tasks, and had fewer liver problems than untreated SMA mice.
“Overall, our results suggest liver-SMN protein depletion is likely contributing to central and peripheral pathologies [disease-related processes] in SMA and highlights the importance of understanding peripheral defects to maximize clinical outcomes,” researchers in Canada and Switzerland wrote.
The study, “Liver SMN restoration rescues the Smn2B/- mouse model of spinal muscular atrophy,” was published in eBioMedicine.
SMA has been historically thought of as a neuromuscular disease. In most patients, mutations in the SMN1 gene result in little to no SMN protein being made, leading to the degeneration of motor nerve cells involved in voluntary movement.
SMN is also found in other major organs, including the liver, where its function isn’t fully understood. Research suggests fatty liver disease may be a common complication of SMA. Mutations in SMN1 might also give rise to alterations in liver fat metabolism.
With the advent of effective disease-modifying therapies that extend patients’ lifespan, SMA patients may need therapies that target disease complications that extend beyond the central nervous system, that is, the brain and spinal cord, to peripheral tissues and organs.
“To be able to address peripheral pathologies therapeutically, we must first know the individual contribution of each tissue to SMA,” wrote the researchers, who used a genetically modified mouse model with reduced levels of the SMN1 protein due to a mutation in the SMN1 gene to better understand less well-characterized damage from SMA. The gene therapy’s effects were assessed at several timepoints up to 100 days after birth.
Effects of gene therapy that targets the liver in SMA
SMA mice that received the liver-specific gene therapy had increased weight, neuromuscular coordination, and lived longer than the untreated SMA mice, who displayed significant fat buildup in their liver and had elevated triglyceride levels, a sign of poor liver functioning and fatty liver disease. Gene therapy prevented lipid accumulation in the liver, rescued fatty liver-related changes, and normalized triglyceride levels.
This liver-specific gene delivery of SMN1 didn’t stop the loss of motor nerve cells in the spinal cord, which were still reduced in SMA mice after treatment. But treated SMA mice did show partial benefits at the neuromuscular junction, which is where motor nerve cells communicate with muscle fibers.
Given that muscle loss is a symptom of SMA, the researchers also examined how liver-specific gene therapy affected the muscles of SMA mice. They found that muscle growth was restored in those that received the gene therapy, with an increase in muscle cell size. Treated mice still showed muscles “in a state of immaturity or repair,” however, the researchers noted.
Untreated SMA mice also have pancreatic problems, with fewer cells that make insulin. Treatment with liver-specific gene therapy increased the number of insulin-producing cells.
Untreated SMA mice also had lower levels of the protein IGF-1, a hormone that helps with tissue growth and plays a key role in the central and peripheral nervous systems, the investigators said. IGF-1 levels were restored after gene therapy.
Increasing IGF-1 could explain how a gene therapy that selectively delivers SMN1 to the liver could have wide-ranging benefits such as improvements in the muscles and pancreas.
“The impact, shown in this study, of liver SMN protein restoration on whole-body pathology demonstrates the importance of liver- intrinsic SMN protein and suggests the liver could be having a broader impact on pathology than previously thought,” the researchers wrote.
