Spinraza May Restore Development of Motor Neurons in SMA Children
Spinraza (nusinersen) may restore the normal development of motor neurons — the nerve cells responsible for making muscle cells work — in children with spinal muscular atrophy (SMA), particularly those who start treatment early, a study found.
Besides getting motor neurons back onto their developmental trajectory, Spinraza also may slow their degeneration.
“Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases,” the researchers wrote.
The study, “Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen,” was published in The Journal of Physiology by a team in Australia.
People with SMA do not make enough of the survival motor neuron (SMN) protein needed for motor neurons to function properly. Spinraza, a therapy developed by Biogen that is approved for all types of SMA, works by allowing cells to make more of SMN.
For children, taking Spinraza can mean being more likely to meet motor milestones — such as holding their head up, rolling over, sitting, or standing — and to survive than those going without treatment. “Importantly, the magnitude of clinical benefit is associated with early initiation of treatment,” the researchers wrote.
While some of its clinical benefit occurs by keeping motor units — the combination of individual motor neurons and the muscle fibers they innervate — healthy, it is not known whether Spinraza also acts on axons. An axon is the portion of a nerve cell that carries electrical impulses to another neuron or other cells.
To shed more light on this question, the researchers decided, as a first step, to look at how electrical impulses in axons change in children with SMA before starting treatment. They measured axonal excitability, or the ability to respond to a stimulus and fire a signal, of the median nerve in the wrist of two groups of children.
The study included 24 children with SMA types 1–3 and at a median age of 6.8, ranging from 4 months to 16 years old. They had been diagnosed with the disease for a median of about five years, and all were symptomatic. It also included 71 age-matched healthy children as controls.
While the pattern of axonal maturation was similar in these two groups, children with SMA showed decreases in the ability of axons to respond to a stimulus and generate an electrical impulse, indicating delays in axonal maturation. The greatest delays were seen in early childhood, or in children 3 years old and younger.
“Whilst motor axons continue to mature in SMA, developmental delays … occur especially in early childhood. Concurrently, motor axons actively undergo degeneration,” the researchers wrote.
Compared with controls, the axons of children with SMA also took longer to recover after firing a signal, meaning the cells needed to wait longer until they were able to respond to a new stimulus. In turn, the ability of muscle cells to respond to a motor nerve decreased.
“Axonal loss and functional abnormalities of motor axons are evident in children with SMA, with changes established early in development,” the researchers wrote. “These processes persist into mid and late childhood, but developmental patterns were sustained in surviving peripheral motor axons in SMA, similar to healthy children.”
Next, the researchers looked at how 18 of the children with SMA responded to Spinraza treatment over time. They found that Spinraza increased the ability of axons to fire signals as well as the ability of muscle cells to respond to a motor nerve, with the most obvious changes seen in younger children who started treatment early.
Overall, “nusinersen [Spinraza] restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation,” the researchers wrote.
These findings also support the importance of newborn screening for SMA, the team added.
“Our study indicates that capturing the developmental potential of the motor axon and reversing axonal degenerative processes, to promote axonal maturation and survival, respectively, are also time-dependant,” the scientists concluded, and this provides a “further rationale for clinical frameworks such as newborn screening for SMA as a gateway for early screening, diagnosis and therapeutic intervention of the condition.”
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