New ASO Compounds Show Potential as Systemic Therapy for SMA, Study Shows

New ASO Compounds Show Potential as Systemic Therapy for SMA, Study Shows

Subcutaneous administration of a new class of antisense oligonucleotide (ASO) compounds called tricyclo-DNA may be an efficient therapy for spinal muscular atrophy (SMA), according to a study in mice.

SMA is an inherited disorder caused by mutations in a gene called SMN1 that encodes the protein SMN. The absence of this protein severely affects motor neurons and, as a result, the overall motor and respiratory functions of a patient will progressively decay.

Previous studies have demonstrated that an alternative gene called SMN2 can lessen the effects of a lack of SMN1. These genes have a very similar genetic sequence. However, the small difference is enough to induce a molecular process called splicing, which prevents the correct reading of the SMN2 sequence and the production of a functional protein. This “natural” deleting process can be reverted by compounds called ASOs, which will prevent the splicing event.

Spinraza (nusinersen) was the first ASO-based therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of SMA. Despite the clear benefits it provides to patients, this therapy has some limitations, including its inability to cross the blood-brain barrier to reach the central nervous system (CNS). To overcome this, Spinraza is administrated directly to the spinal canal, which can represent clear technical and clinical challenges.

The study, “Efficient SMN Rescue following Subcutaneous Tricyclo-DNA Antisense Oligonucleotide Treatment,” was published in the journal Molecular Therapy – Nucleic Acids.

Researchers tested the therapeutic potential of a new class of ASOs, called tricyclo-DNA or tcDNA. In previous studies these compounds showed improved potential to bind to DNA and RNA molecules, and also to be able to pass the blood-brain barrier. These findings suggest that tcDNA may show promise as systemic therapies for SMA.

The research team tested the efficacy of two compound of the tcDNA class in animal models of mild type 3 SMA. They found that subcutaneous injection of the compounds restored the levels of SMN2 in all tissues, including the CNS. In addition, tcDNA treatment improved the animals’ respiratory function.

“It is still debated how SMN deficiency leads to peripheral pathology, but the major goal of a tcDNA-based therapeutic strategy is to achieve systemic efficacy to ensure the best resolution of disease in SMA patients,” the researchers wrote.

Based on the study’s findings, tcDNA compounds were shown to provide therapeutic benefits without requiring invasive administration methods or anesthesia. “tcDNA could therefore represent a particularly attractive AON therapy for SMA requiring whole-body treatment,” they wrote.

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