A specific chemical modification of antisense oligonucleotides (ASOs) — called MOE; used in Spinraza (nusinersen) — was more effective than another commonly used modification — called PMO — in improving survival and motor neuron preservation in a mouse model of severe spinal muscular atrophy (SMA).
These findings highlight the therapeutic potential of MOE-ASOs in SMA, and suggest that PMO-ASOs likely require higher doses or more frequent dosing to achieve comparable effectiveness.
The study, “Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model,” was published in the journal Nucleic Acids Research.
SMA is caused by mutations in the SMN1 gene that result in low or no production of SMN, a protein essential for motor neuron health. While a second survival motor neuron gene (SMN2) is capable of producing SMN, an event called “alternative splicing” limits the amounts of functional SMN it produces to 10% to 15%, and is usually unstable and quickly degraded.
Alternative splicing allows for a single gene to give rise to many different proteins. Just like in a recipe, adding or removing certain key ingredients — in this case bits of genetic information — can change what results.
Certain chemical modifications help with ASO stabilization, target binding, and therapeutic effects. Two types of chemical modifications — 2′-O-methoxyethyl (MOE), used in Spinraza, and phosphordiamidate morpholino oligomer (PMO) — in ASOs targeting the same SMN2 region were shown to effectively ease symptoms and extend the lifespan of SMA mouse models.
“However, to date, no thorough head-to-head comparison of the efficacy of the two modifications … in SMA mouse models has been performed, and therefore, it is unclear if one of the modifications might be more advantageous for SMA therapy,” the researchers wrote.
Moreover, determining which chemical modifications result in greater therapeutic benefits may help to design or optimize ASO-based treatments for SMA and other diseases.
Researchers set out to compare the therapeutic efficacy of these two modifications in ASO10-29 — an ASO similar to Spinraza and previously shown to be effective in SMA mouse models — in a mouse model of severe SMA (mean survival of 10 days).
Newborn pups were treated with either MOE-ASO (low or high dose) or PMO-ASO (low or high dose) through a subcutaneous (under-the-skin) injection. These doses corresponded to equivalent concentrations between the two ASOs.
Results showed that both ASOs effectively corrected SMN2 splicing in several disease-relevant tissues, improved motor function, and dramatically extended survival of treated mice in a dose-dependent manner, compared to those given a harmless saline solution.
However, MOE-ASO treatment resulted in more sustained effects, including greater gains in body weight, lesser motor neuron death, and longer survival.
Notably, based on the levels of SMN2 splicing correction, PMO-ASO appeared to have a faster onset of action and a greater ability to reach the brain than MOE-ASO. But its effects were not as long-lasting as those of MOE-ASO across all evaluated tissues.
These findings suggest that MOE-ASO’s greater therapeutic benefits may be associated with its ability to stay longer in the body.
“We conclude that both [MOE] and [PMO] chemistries are effective for splice-switching ASOs to treat SMA mice, though the latter may require higher doses or more frequent dosing to achieve similar [disease] rescue,” the researchers wrote.
Nevertheless, the team highlighted that PMO-ASOs may be a good therapeutic option for certain diseases, and particularly those affecting the skeletal muscle, since PSO-ASO was more readily taken up by skeletal muscle fibers than MOE-ASO in their study.
The fact that MOE-ASO’s activity remained high in disease-relevant tissues one month after a high-dose administration, the researchers also noted, suggests that ASOs have the potential to treat a broad spectrum of diseases.
“As novel ASO-modification chemistries continue to emerge, a new modification or a combination of different chemistries could potentially result in even greater efficacy and tolerability for various applications,” they concluded.
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