Spinraza helps restore key amino acid imbalance in severe SMA
Study finds reduced L-arginine levels in SMA and suggests supplementation
Spinraza (nusinersen) helps correct a key amino acid deficiency in people with a severe form of spinal muscular atrophy (SMA), a study has found.
Researchers found that the treatment restores levels of L-arginine, an amino acid important for brain development that is reduced in the brainstem and spinal cord of a mouse model of SMA and in the cerebrospinal fluid of SMA patients.
“Our findings highlight the clinical relevance of amino acid metabolism in SMA and emphasize the need to explore complementary therapeutic strategies, including amino acid supplementation, to overcome SMA-associated metabolic dysfunction and improve treatment efficacy,” they wrote.
The study, “Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy,” was published in the journal Neurobiology of Disease.
SMA is chiefly caused by mutations in the SMN1 gene, which contains instructions for producing the survival motor neuron (SMN) protein. A deficiency of this protein leads to the degeneration of the nerve cells responsible for controlling movement, or motor neurons. However, studies using animal models indicate the clinical presentation of SMA cannot be fully explained by mechanisms that occur exclusively within motor neurons.
Imbalance of amino acids in SMA
Studies have shown an imbalance of amino acids that influence neurological function — called neuroactive amino acids — in SMA. L-arginine has multiple effects in the brain, namely in how the connections between neurons adapt, in cell-to-cell communication, and in linking cellular energy metabolism and motor neuron resilience.
Still, “little is known about how SMN deficiency alters amino acid metabolism in the CNS [central nervous system, which includes the brain and spinal cord],” the researchers wrote, particularly as to whether L-arginine is a potential metabolic signature of disease severity.
A team led by scientists in Italy set out to determine the levels of L-arginine in the CNS of SMA patients and of a mouse model of severe disease and whether treatment with Spinraza might restore L-arginine balance.
In mice, a significant decrease in L-arginine was detected in the brainstem, a region at the base of the brain that regulates vital functions (e.g., heart rate, respiration) and relays sensory and motor information, at both early and later symptomatic stages of the disease. A trend toward decreased L-arginine in the spinal cord was observed at later stages, while no significant changes were noted in other brain regions at any stage.
The researchers then assessed whether patients with different types of SMA who had not received any therapy also showed reduced L-arginine in their cerebrospinal fluid (CSF, the fluid surrounding the brain and spinal cord).
They measured the levels of L-arginine in 29 patients with SMA type 1, 19 with SMA type 2, and 13 with SMA type 3. Those with the more severe type 1 disease showed significantly reduced L-arginine levels in the CSF compared to individuals who did not have SMA and served as controls, and patients with SMA type 2 or 3.
Then, the investigators assessed whether the levels of L-arginine of SMA type 1 patients were rescued by clinical interventions, namely the use of a feeding tube, ventilation, and tracheostomy, which is a surgical procedure to create an opening in the neck and into the windpipe to help with breathing. Results showed no differences in L-arginine levels. No analysis was conducted for the other disease types due to the small number of patients.
Next, the findings showed that Spinraza treatment significantly increased L-arginine levels in the CSF of SMA type 1 patients, but not in type 2 or 3 patients. Also, no correlation was found between L-arginine levels and motor functions across all SMA types. In SMA type 2, L-arginine levels decreased as patients got older.
Overall, “our results demonstrate a dysregulation of L-arginine in SMA and highlight a role for SMN-enhancing therapies [Spinraza] in restoring neurochemical alterations observed in patients with this neurodegenerative disease,” the study concluded.
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