New HDAC inhibitor AR42 shows promise in SMA mouse model

Experimental molecule seen to ease symptoms, prolong survival in mice

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A human hand is shown holding a mouse alongside a rack of vials filled with liquid.

A histone deacetylase (HDAC) enzyme inhibitor called AR42 was found to prolong survival and ease motor symptoms in a mouse model of spinal muscular atrophy (SMA).

While scientists initially expected the experimental molecule to show benefits by helping to boost levels of the SMN protein that’s deficient in SMA, it instead appeared to exert neuroprotective effects that were SMN-independent.

“In this study, we demonstrate in vivo [in the body] efficacy of a novel, orally bioavailable HDAC inhibitor, AR42, in a mouse model for SMA,” the researchers wrote, adding “AR42 treatment does increase survival and delay spinal motor neuron loss in [these] SMA mice.”

Further testing is needed, but the scientists believe AR42 could be combined with other SMN-boosting therapies to maximize therapeutic benefit for human patients.

The study, “Evaluation of the orally bioavailable 4-phenylbutyrate-tethered trichostatin A analogue AR42 in models of spinal muscular atrophy,” was published in Scientific Reports.

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HDAC inhibitor works unexpectedly in SMA mice

In the most common types of SMA, mutations in the SMN1 gene result in a lack of functional SMN protein. As a consequence, motor nerve cells degenerate and symptoms of progressive muscle weakness and wasting ensue.

An SMN-producing gene called SMN2 can act as a backup in people with the rare disorder. The number of copies an individual has of SMN2 influences the person’s disease severity, with more copies linked to more SMN protein and less severe disease.

As such, treatments to boost SMN2 activity, thus increasing SMN levels, are of interest for SMA. Indeed, two of the three approved SMA therapies in the U.S. — Evrysdi (risdiplam) and Spinraza (nusinersen) — aim to increase SMN2 activity.

Molecules that inhibit or block histone deacetylase (HDAC) enzymes, such as trichostatin A (TCA) and 4-phenylbutyrate (4PBA) also have been shown to boost SMN2 activity in preclinical studies. Both TCA and 4PBA have been found to increase survival in SMA mouse models, thus suggesting that an HDAC inhibitor could be of benefit alone or combined with other SMA therapies.

HDAC inhibitors are substances that block the activity of a group of enzymes called histone deacetylases. These enzymes are responsible for removing acetyl groups from proteins called histones, which are involved in the packaging of DNA within our cells.

AR42 is a new HDAC inhibitor consisting of a more potent analogue of TCA tethered to 4PBA. It has shown therapeutic potential in preclinical and clinical studies for various forms of cancer, but had not been evaluated for SMA.

Now, researchers examined the effects of AR42 in SMA patient cells and a mouse model.

A gene’s promotor is a piece of DNA that works to activate the gene. Greater gene activity is, in turn, generally expected to mean that more of its protein product will be produced. While SMN2 promotor activity was elevated in SMA patient cells with AR42 treatment, there was no evidence of increased SMN protein production.

Still, structures in the cells’ nucleus, called gems, exhibited greater positivity for SMN protein with AR42. That indicated that the treatment works to boost localization of SMN in the cell’s core even if it does not overall increase SMN levels.

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AR42 tied to 27% increase in survival in mice

In a mouse SMA model, oral treatment with AR42 prior to symptom onset led to a significant 27% increase in survival. Specifically, untreated mice survived an average of 15.8 days, whereas those given AR42 survived for 20.1 days. The onset of body mass loss also was delayed by 31%

Only treatment initiated before the emergence of symptoms was able to prolong survival, the researchers noted.

Small molecule HDAC inhibitors … offer another SMN-independent protective strategy that could be used in concert with SMN2 inducers to maximize therapeutic outcomes in SMA patients.

The treatment also improved motor function in the mouse model, although motor deficits were still evident. Correspondingly, AR42-treated mice lost fewer motor nerve cells in the spinal cord than their untreated counterparts.

Interestingly, while HDAC activity was found to be significantly inhibited in the spinal cord of the mice, SMN protein levels were not impacted, nor was the activity of genes dependent on SMN. Those findings suggest that the benefits of AR42 may be unrelated to SMN increases.

Still, HDAC inhibitors are tied to other neuroprotective actions. Here, the scientists identified that AR42 led to activation of Akt, a known neuroprotective pathway in SMA models. It’s believed to be protective by inactivating a protein called GSK3-beta.

Overall, “small molecule HDAC inhibitors … offer another SMN-independent protective strategy that could be used in concert with SMN2 inducers to maximize therapeutic outcomes in SMA patients,” the researchers concluded.