Study examines gene activity changes in LOPD
Differences in skeletal muscles normalized after six months of Nexviazyme
Late-onset Pompe disease (LOPD) patients exhibit significant gene activity changes in their skeletal muscles compared with healthy people, some of which were normalized after six months of Nexviazyme (avalglucosidase alfa) treatment, a study found.
Pathways involved in lysosome function, energy metabolism, and inflammation appeared to be most altered, many of which overlapped with findings from a previous study in infantile-onset Pompe disease (IOPD) patients.
“This study provides further insight into Pompe disease biology and demonstrates the positive effects of avalglucosidase alfa [Nexviazyme] treatment,” the study’s researchers wrote.
The study, “Transcriptomic characterization of clinical skeletal muscle biopsy from late-onset Pompe patients,” was published in the journal Molecular Genetics and Metabolism.
Pompe disease is caused by mutations in the GAA gene, leading to defective —or no — production of the GAA enzyme. As a result, a large sugar molecule called glycogen builds to toxic levels inside cells, especially skeletal and cardiac muscle cells.
IOPD is characterized by little to no GAA activity and has more severe symptoms, whereas when some GAA activity remains, it results in LOPD, a less severe form of Pompe with a later disease onset.
In Pompe, enzyme replacement therapy (ERT), namely Lumizyme (alglucosidase alfa) or Nexviazyme, aim to provide patients with a lab-made version of the GAA enzyme. Both therapies are marketed by Sanofi.
In the study, researchers from Sanofi investigated differences in gene activity, or expression, in the skeletal muscles of LOPD patients compared with healthy people, and how that gene activity profile changed in LOPD patients after six months of Nexviazyme treatment.
Their goal was to better understand the cellular processes that are disrupted in Pompe, and how ERT influences them.
Muscle biopsies
The analysis was conducted on muscle biopsies from eight LOPD patients enrolled in the NEO1 Phase 1 trial (NCT01898364) of Nexviazyme, obtained before starting treatment and again six months after. Muscle biopsies from 10 healthy people, who served as controls, also were examined.
Results showed that global gene activity differed between pre-treatment LOPD patients and healthy people, with thousands of genes at either higher or lower levels in LOPD compared with controls.
After six months of treatment, 3,235 (54.5%) of genes whose activity was initially increased showed a reduction of least 1.2-fold compared to baseline (study start), with 166 (2.34%) being significantly reduced. Conversely, among genes with lower activity relative to controls, treatment led to an increase of at least 1.2-fold in 4,128 genes (64.7%) and a significant increase in 467 (6.57%).
Notably, among thousands of genes, only two exhibited a worsening dysregulation after six months of Nexviazyme, “consistent with the ability of [Nexviazyme] to slow or halt the progression of disease,” the researchers wrote.
Significant variability in gene activity was observed in individual patients both before starting treatment, and afterward, which is in line with variability in disease severity and treatment responses seen in LOPD patients, according to researchers.
In general, patients who exhibited the strongest gene dysregulation prior to treatment also had more severe clinical presentations, and exhibited the strongest gene activity corrections with Nexviazyme treatment.
Overall, many genes associated with the LOPD signature were involved in pathways related to energy metabolism, skeletal muscle regeneration, and immune signaling.
Lysosome function
A deeper analysis revealed that pathways involved in lysosome function and production were dysregulated in LOPD patients both before and after treatment. Lysosomes are the cellular compartments involved in clearing cellular waste. Glycogen accumulates in Pompe cells as lysosomal function becomes impaired.
Energy metabolism pathways also were altered in Pompe patients. Since glycogen is normally used for energy, the body’s inability to break it down leads to a need for cells to use alternative energy sources.
Consistently, certain energy pathways were enriched in Pompe patients and largely did not improve after six months of ERT, although some, particularly those involved in lipid (fat) metabolism, did show trends toward  normalization.
A previous study performed a similar gene expression analysis in skeletal muscle biopsies from IOPD patients before and after receiving Myozyme (Lumizyme in the U.S.) for one year, revealing disruptions in muscle and inflammatory pathways.
Comparing those findings to the current study, the researchers found that IOPD patients exhibited similar alterations to lysosomal and energy metabolism pathways as LOPD patients.
Likewise, both patient groups — as well as patients with Duchenne muscular dystrophy, another progressive muscle disease — exhibited significant changes in inflammatory pathways, although each was associated with its own inflammatory signature.
The researchers noted that peak ERT efficacy with Lumizyme usually is reached after two to three years of treatment, which was outside the scope of the study.
Still, within these six months, many patients already experienced clinical improvements, suggesting that the modest gene expression normalization observed here “would continue with long-term treatment,” the researchers wrote.
The team also noted the importance of a consistent ERT treatment regimen. Because clinical declines are observed when treatment stops, it’s likely gene expression changes also would occur “with even brief interruptions in treatments,” the team wrote.
About the Author
