• In a recent study, researchers made a chemical change to a molecule used to treat spinal muscular atrophy (SMA).
• Researchers believe this change could improve SMA treatments, making them safer, more effective, and longer-lasting.
• A new study is being designed to test these findings.

Recent study results may provide the framework for developing new SMA treatments that are safer and require fewer injections. The study, published in June in the journal Nucleic Acid Therapeutics, focused on a new change in the chemistry of a molecule known as an antisense oligonucleotide. The study was led by researchers at the Moscow-based Skolkovo Institute of Science and Technology (Skoltech).

Antisense oligonucleotides are DNA or RNA fragments that have been modified to bind to molecules of RNA and modify the production of proteins. Spinraza (nusinersen), a therapy approved by the U.S. Food and Drug Administration to treat SMA, uses antisense oligonucleotides to modify the genetic changes that cause SMA.

In people with SMA, mutations to the SMN1 gene inhibit the production of survival motor neuron (SMN) protein, which is necessary for healthy muscle growth and function. Nusinersen is believed to work by increasing the production of SMN protein.

According to prescribing information, nusinersen — sold as the brand name Spinraza — is administered in an initial series of four loading doses and then once every four months. Warnings about kidney toxicity and bleeding complications are listed on the drug’s label.

A key element of nusinersen’s ability to treat SMA is a chemical group attached to the nusinersen oligonucleotide, the phosphorothioate group. However, the version of this chemical group used in nusinersen is also believed to contribute to its potential side effects.

In the Skoltech study, researchers experimented with replacing the phosphorothioate group with another chemical group, known as methanesulfonyl (also called mesyl or μ — pronounced “mu”) phosphoramidate.

Researchers tested the mesyl phosphoramidate version of the antisense oligonucleotide — dubbed “μ-oligo” — both in a mouse model and in cells sourced from human volunteers with SMA. Results showed that the μ-oligo could be safer to use, which may allow it to be administered in higher doses. At higher doses, the μ-oligo is expected to be equally effective and longer-lasting. These improvements may lead to the development of a safer, more effective drug for SMA that requires less frequent doses.

In the study, the new chemical compounds were tested in neonatal mouse models and in cells grown in labs from cells donated by people with SMA. Skoltech and its research partners are currently planning a follow-up study designed to test these new findings more extensively.

Skoltech was established in 2011 in partnership between nine Russian universities and the Massachusetts Institute of Technology (MIT). Several other academic institutions, including Lomonosov Moscow State University, Novosibirsk State University, Serbsky National Medical Research Center for Psychiatry and Narcology, the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, and Oxford University, also contributed to this research.

Read more about existing treatments for SMA.