Antibody-ASO Conjugate System Improves Survival in SMA Mice

ASO targeted the SMN2 gene, much like Spinraza does

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration of a mouse in a lab.

A new system that contains a gene-modulating therapy attached to an antibody that enables crossing into the nervous system improved survival outcomes in a mouse model of severe spinal muscular atrophy (SMA), a new study reports.

The study, “Antibody-oligonucleotide conjugate achieves central nervous system delivery in animal models for spinal muscular atrophy,” was published in JCI Insight.

Antisense oligonucleotides, or ASOs, are a recently developed class of medications that contain a small piece of DNA or RNA that can bind to genetic material inside a cell, modulating the activity of specific genes.

The first therapy approved to treat SMA, Spinraza (nusinersen), contains an ASO that modulates the “backup” SMN2 gene to increase production of the SMN protein. SMA is mainly caused by mutations in the SMN1 gene that produces most SMN, a protein needed for the survival of motor neurons — the nerve cells that control movement.

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While ASOs can be highly effective once inside a cell, getting them to cells in affected tissue can be a challenge. In particular, the central nervous system (brain and spinal cord) is surrounded by cellular barriers that regulate what substances can get in and out. This helps keep the nervous system safe from toxins, but also can prevent ASO-based medicines from getting to motor neurons in the spinal cord.

To get around this problem, Spinraza is administered via injection directly into the lower spine. This strategy has several drawbacks, however. It typically results in less medication getting to higher parts of the spine or brain and little medication gets to tissues outside the nervous system that can also be affected by SMA, such as skeletal muscle and liver. The procedure also is fairly invasive and injection into the spine is not feasible for some patients with spinal issues such as scoliosis.

A research team in the U.K. sough to create an ASO system that would be able to cross into the nervous system so it could be administered systemically (i.e., injected into the bloodstream) to all the body’s tissues. It used an ASO that targeted the SMN2 gene, much like Spinraza.

“A systemically administered ASO delivery system with biological activity in brain and spinal cord as well as in peripheral tissues is required to facilitate optimal treatment in all SMA patients,” the researchers wrote.

Crossing the nervous system

The new system involves attaching the ASO to an antibody called 8D3130, which targets a protein called the transferrin receptor (TfR), expressed on the blood vessel cells around the nervous system.

The TfR protein receptor normally helps transport iron into the nervous system. By binding to it, 8D3130 can stimulate uptake into the nervous system through similar biological pathways. The 8D3130 antibody was developed to have an optimum level of “stickiness,” so it would bind to TfR enough to get into the nervous system, but then would disengage from it to deliver a payload to nervous system tissues.

After creating this system and performing a battery of pharmacological tests, the researchers tested its effectiveness in a mouse model engineered to carry the human SMN2 gene.

Results showed the ASO-8D3130 antibody conjugate led to an increase in SMN protein produced by the gene in the brain and spinal cord, by 80% at the highest dose tested. By contrast, the ASO attached to a control antibody had no effect on SMN levels in the nervous system.

Along with being active in the nervous system, the ASO-8D3130 system also increased SMN production in the kidneys and liver, as well as in skeletal muscles, which are those involved in movement.

“Neuromuscular diseases typically require therapies to target skeletal muscles. SMA in particular has also been shown to affect the liver and kidney tissues. Therefore, a potential advantage of a systemically administered drug treatment would be its activity within these tissues,” the researchers wrote.

The system was then tested in a mouse model of severe SMA. In untreated mice, median survival time was seven days. In mice given the ASO attached to a control antibody, median survival time was 12 days. In mice treated with the ASO-8D3130 system, median survival was 24 days.

“In addition to improved uptake into the [central nervous system] and peripheral tissues, [ASO-8D3130] also rescued survival in a severe mouse model of SMA,” the scientists said, emphasizing that more work, including detailed toxicology studies, was needed before before the therapy could be brought to the clinic. They said their study “provides a proof of concept for therapeutic, systemic dosing of antibody-ASO conjugates.”

The researchers involved in this study included several scientists at AstraZeneca and PepGen.