Combining Therapies May Improve Efficacy in SMA: Mouse Model

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by Steve Bryson PhD |

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A combined spinal muscular atrophy (SMA) therapy — one incorporating two treatments targeting different disease processes related to the SMN protein — showed improved efficacy over single treatments in a mouse model.

The findings support further research into combination treatment strategies, the researchers said. A combined therapy could potentially reduce the number of patients who fail to respond to current singular regimens, or widen the therapeutic range of available treatments.

In the study, a therapy designed to elevate levels of SMN protein, which are abnormally low in SMA, was combined with a compound that prevented SMN breakdown. Together, they synergistically enhanced SMN levels, rescued nerve damage, and improved motor function, weight gain, and survival.

The study, “A combinatorial approach increases SMN level in SMA model mice,” was published in the journal Human Molecular Genetics.

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SMA is caused by the reduced production of the SMN protein in motor neurons, the specialized nerve cells that control voluntary muscle movement. A lack of SMN leads to progressive muscle weakness and shrinkage, or atrophy, which mainly affects motor function. But it also can impact speaking, swallowing, and breathing.

Current disease-modifying therapies, designed to increase SMN levels, have dramatically improved survival and motor function in SMA. The efficacy of these therapies can vary from patient to patient, however.

Research has suggested that combining therapies may be an effective strategy for generating stable amounts of SMN protein across different patients. The aim is to target complimentary disease-related mechanisms.

A team based at the F. Edward Hebert School of Medicine at the Uniformed Services University of the Health Sciences, in Maryland, showed how a small molecule called ML372 selectively blocked the breakdown of SMN protein, improving motor function and survival in an SMA mouse model with severe disease.

Building on these findings, the researchers now investigated the impact of ML372 combined with an antisense oligonucleotide (ASO) therapy in a mouse model of SMA. An ASO is a type of RNA-based treatment designed to increase levels of SMN. Of note, Spinraza (nusinersen), by Biogen, is an ASO therapy approved for children and adults with SMA.

First, cells derived from SMA patients were treated with the ASO, ML372, or both. Compared with untreated control cells, ML372 alone doubled the levels of SMN, while the ASO alone increased SMN 1.5 times. The combination of ML372 and ASO significantly increased SMN levels over each individual treatment.

The team then conducted a similar experiment in an SMA mouse model that carried a defective SMN1 gene that encodes for SMN protein. These mice display reduced SMN expression, or production, in all tissues, as well as severely impaired motor function, reduced body weight, and a 14-day lifespan.

Similarly, compared with the single-treated group, co-treated mice had significantly higher SMN levels in muscle and spinal cord tissue. Combined treatment also rescued motor neuron size and number in the spinal cord and increased numbers of muscle fibers.

“Together these data provide strong evidence that SMN protein expression can be further increased by targeting complementary pathways,” the team wrote.

Next, the supply of nerve fibers to the neuromuscular junction (NMJ) — where nerves connect to the muscles they control — was examined. In SMA mice, the nerve supply to the NMJ in abdominal muscles was markedly reduced, or denervated.

With ML372 or ASO treatment, the percent of fully supplied, innervated NMJs increased from partially innervated and lowered the percent of fully denervated NMJs in the abdominal muscles. Co-treatment demonstrated a significant shift from partially to fully innervated NMJs and reduced the percent of denervated NMJs to that of healthy mice.

To test motor function, mice were placed on their backs, and the time for them to turn themselves over was measured (up to 30 seconds). Co-treated animals showed significantly faster turnover times compared with ML372- or ASO-treated animals — times close to those of healthy mice.

Lastly, compared with individual treatment, weight gain with mice given the combined therapy was found to be indistinguishable from healthy mice. The animals lived for 80 days on average versus 30 days with ASO alone. ML372-treated mice showed no extended survival at the dose used.

“The current goal of SMA therapy is to maintain the gains that have been achieved through the approved SMN boosting therapies,” the researchers wrote. “We show here that a compound that slows SMN degradation can synergistically enhance SMN levels to further improve the SMA phenotype in mice.”

“This pathway offers an additional therapeutic modality to potentially reduce the number of non-responders and broaden the therapeutic range of current treatments,” they concluded.