Cell ‘Cleaning System’ Could Be Alternative Target for SMA Therapies, Scientists Say

A pathway known as the cell’s “cleaning system” may be a promising target of alternative approaches to treating spinal muscular atrophy (SMA) — ones that look beyond the disease-causing mutation.

This possibility is the focus of the perspective article, “Autophagy inhibition: a new therapeutic target in spinal muscular atrophy,” published in Neural Regeneration Research.

Autophagy is an important process by which cells degrade or recycle components that are damaged or no longer needed.

Cells use autophagy as a housekeeping “cleaning system” and to get rid of toxic materials, such as proteins damaged by  disease and microbes.

Materials to be destroyed are delivered by vesicles to cell compartments called lysosomes, where degradation takes place.

But when autophagy is dysregulated and turns overactive, it can damage cells severely, even cause them to die — including motor neurons or nerve cells.

In mouse models of SMA, the authors noted — referring to their work and the work of other scientists — high numbers of apparently inactive autophagy vesicles were seen to accumulate in the animals’ motor neurons, leading to their premature death. 

For this reason, the researchers — with the department of neuroscience at the University of Torino in Italy — hypothesize that inhibiting autophagy may delay SMA progression. 

Treating the brains of these mice with an autophagy inhibitor, called 3-methyladenine (3-MA), was shown to have neuroprotective effects. Namely, the treatment slowed autophagy, which in turn reduced cell death and improved the survival of motor neurons in the animals’ spinal cord.

Treatment also led to modest but significant improvements in lifespan, and delayed motor decline in the diseased mice compared with untreated control mice.

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“We suggest for the first time that inhibition of this process by ICV [intracerebroventricular] administration of 3-MA have a significant impact on disease progression, making autophagy a novel and intriguing therapeutic target,” the two researchers wrote.

“Overall, our work strongly suggests that autophagy inhibition plays a protective role in SMA,” they wrote.

Therapy development to date has largely focused on correcting defects in the survival motor neuron 1 (SMN1) gene that are the cause of the disease. Spinraza, the only currently approved SMA treatment (by Biogen), is an antisense oligonucleotide (ASO) that increases the expression of a functional SMN protein.  

Another gene therapy candidate being developed by AveXis, called AVXS-101, is advancing in pivotal clinical trials.

In the researchers’ perspective, all of these therapies are “SMN-dependent strategies, although it is now clear that further cellular mechanisms can affect the severity of SMA.”

Moreover, since none of these current strategies “aimed at restoring SMN is completely effective in arresting the disease progression, it is evident” that combination approaches “are needed, keeping in mind the complexity of additional molecular pathways contributing to SMA pathogenesis,” the researchers said.

SMA, they note, is increasingly seen as a multisystem disorder. As such, synergic treatments aimed at both increasing SMN expression (like Spinraza) and preventing disease progression (therapies with non-SMN targets and SMN-independent mechanisms) are “clearly essential,” they argue.

The researchers added that SMA patients with milder disease are not eligible for gene therapy trials, and “alternative treatments should be rapidly provided for such individuals.”

“[T]herapies targeting other molecular pathways (such as the autophagic process) are strongly required, alone or in combination with the emerging gene therapy and antisense oligonucleotide approaches in order to assure the most effective treatment to all the SMA patients,” the two researchers concluded.