SMA Treatment May Be More Effective by Altering Underlying Molecule

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by Marisa Wexler MS |

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Biochemical modifications made to antisense oligonucleotides — molecules that are the basis of an existing therapy for spinal muscular atrophy (SMA) — may improve this and similar treatments, new research suggests.

More work, which is underway, is needed as the biochemical changes seen to possibly offer an advantage were more effective in lab than in animal studies, its scientists said.

These findings were in the study, “Mesyl Phosphoramidate Oligonucleotides as Potential Splice-Switching Agents: Impact of Backbone Structure on Activity and Intracellular Localization,” published in Nucleic Acid Therapeutics.

Antisense oligonucleotides are small pieces of nucleic acids (DNA or RNA) that are able to target a specific gene’s messenger RNA — the genetic template that gets “read” by the cell’s protein-making machinery when a protein is produced. Depending on its specific design, oligonucleotides can have several effects, making them useful therapeutic tools.

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SMA is caused by mutations in the gene SMN1, which encodes a protein called SMN. The aim of antisense oligonucleotide therapy for SMA is to target a similar gene called SMN2, which also encodes SMN. But due to slight differences in the code, this gene normally does not produce much of the protein or a stable protein.

Targeting SMN2 with the right oligonucleotide can allow for greater SMN production. Spinraza (nusinersen), by Biogen, the first approved SMA treatment in the U.S., works through this mechanism. 

Most oligonucleotide therapies contain a chemical modification called a phosphorothioate group.

According to Timofei Zatsepin, a professor at the Skolkovo Institute of Science and Technology (Skoltech) in Russia and the study’s co-author, this chemical modification is “present in almost all oligonucleotide drugs approved so far.”

The addition of a phosphorothioate group improves the stability of oligonucleotides, allowing them to more effectively move through the body. But this addition also “demonstrates significant toxicity that limits applications of oligonucleotide drugs,” Zatsepin said in a press release.

Researchers at Skoltech and Oxford University in the U.K. assessed a slightly modified version of this chemical modification, called a methanesulfonyl phosphoramidate group, or mesyl for short. Oligonucleotides with this chemical modification are referred to as u-oligonucleotides.

“During the last 30 years, many alternatives [to the long-used phosphorothioate group] were developed, but we do believe that mesyl phosphoramidates are superior to other phosphate mimics in therapeutic oligonucleotides,” Zatsepin said.

Prior research also found u-oligonucleotides to potentially be “much less toxic than PS [phosphorothioate] oligonucleotides,” while still showing promising efficacy.

The research team tested various oligonucleotides, including u-oligonucleotides and Spinraza, in different laboratory models of SMA — both in vitro, using cells in dishes, and in vivo, in living animals (specifically, mice).

Results showed that the different oligonucleotides were similarly effective in vitro; however, u-oligonucleotides were less effective than Spinraza in vivo. Reasons for this difference may have to do with differences in how the compounds are taken up within cells, the researchers found.

“In our study we found that µ-oligonucleotides were active in vitro, while in vivo the efficacy was lower in comparison to nusinersen at the same dose,” Zatsepin said.

“As µ-oligos are more stable and less toxic in vivo than PS oligos,” he added, “we propose that µ-oligos used in higher doses can provide the same efficacy together with more prolonged action — this study is under development now.”

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