Search for Drugs to Treat Spinal Muscular Atrophy Pinpoints Likely Target Enzyme

Neurological disease researchers have identified a target for drugs to treat the hereditary childhood neurodegenerative disorder spinal muscular atrophy (SMA).

SMA is caused by a mutation in the SMN1 (survival motor neuron 1) gene. SMN1 deficiency causes spinal motor neuron degeneration, which results in progressive muscle atrophy and death. The molecular mechanism underlying neurodegeneration in SMA is unknown, and no treatment is currently available to prevent neurodegeneration and reduce the burden of illness.

Investigators at the Texas Tech University Health Sciences Center (El Paso, USA) worked with neuron cultures and mouse models of SMA while searching for possible drug targets that would correct the neurological damage caused by the disorder.

They reported in the December 15, 2015, issue of the journal Human Molecular Genetics that they had identified the c-Jun NH2-terminal kinase (JNK) signaling pathway as being responsible for neurodegeneration in SMA. The neuron-specific protein isoform Jnk3 was required for the neuron degeneration caused by SMN1 deficiency, while lack of Jnk3 reduced degeneration of cultured neurons caused by low levels of SMN1. Genetic inhibition of the JNK pathway in JNK3 knockout mice resulted in relief of SMA symptoms. Jnk3 deficiency prevented the loss of spinal cord motor neurons, reduced muscle degeneration, improved muscle fiber thickness and muscle growth, improved motor function and overall growth and increased lifespan of mice with SMA.

"So far, spinal muscular atrophy research has focused on targeting the genetic mutation to prevent degeneration of spinal motor neurons, but it has not been successful because of challenges associated with gene therapy," said senior author Dr. Laxman Gangwani, associate professor of neurosciences at Texas Tech University Health Sciences Center. "This is the first study done that identifies a target, Jnk3, that is independent of the genetic mutation of spinal muscular atrophy for novel therapeutic development.

"Jnk3 represents a promising new avenue of research for clinical advances in developing a treatment," said Dr. Gangwani. "We saw less muscle degeneration, more muscle growth and better muscle strength, and improvement in overall movement. What were more striking were a four-fold reduction in initial mortality period and a two-fold increase in total lifespan."

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