Study sheds light on SMA treatment and progression

A new study into the severe motor condition spinal muscular atrophy (SMA) has shed light on why the disease progresses, and also suggested potential treatments for the condition.

A team led by Professor Adrian Krainer, from Cold Spring Harbor Laboratory (CSHL), and including scientists from California-based Isis Pharmaceuticals, have used technology known as TSUNAMI to help create the first animal model of the adult-onset version of SMA.

Last year, the team used TSUNAMI to make a mouse model of the disease as it is manifest in children, as Type I SMA is the leading genetic cause of childhood mortality, but on some occasions people develop the symptoms of the illness after they have reached adulthood.

Bearing this in mind, the team worked on the basis that all patients with SMA, regardless of their age, have a non-functional version of a gene called SMN1, which stands for "survival of motor neuron".

The SMN1 gene encodes a protein known as SMN, which motor neurons require in order to function properly, with humans having a backup copy of sorts known as SMN2, which produces the same protein, but in lower amounts.

According to Professor Krainer, the aim of the study was to better understand how insufficient levels of the SMN protein in adulthood causes pathology in different parts of the body.

The team set out to create a model in the adult mouse, using TSUNAMI technology to intensify SMA's pathological processes in mice bred to mimic the less intense forms of the illness.

It can therefore be used to recapitulate the process by which pathology manifests in different places in the body over the lifespan of the model animal.

Dr Kentaro Sahashi, postdoctoral researcher and neurologist and first author of the study, commented: "Our efforts to model the adult form of SMA were successful. We observed delayed onset of motor neuron dysfunction; we noted also that SMN2 mis-splicing increases during the late stages of SMA, likely accelerating its progression in the body.

"We noted, importantly, marked liver and heart pathologies that were related to SMA's progression in adults," he added.

As such, the mouse model suggests that only moderate levels of SMN protein are needed in the adult nervous system for normal function, which means that there may be a "broad time window" in adult Type IV SMA patients in which to intervene with drugs, the experts note.

The study leaders, in conjunction with Isis Pharmaceuticals, have now identified and characterised an antisense oligonucleotide drug, which is currently in Phase 2 clinical trials and may offer hope for sufferers of SMA in the future.