ML372 is an investigational therapy being studied as a potential treatment for spinal muscular atrophy (SMA). It is being developed by a multi-institutional team led by researchers at Uniformed Services University of the Health Sciences in Bethesda, Maryland.

How ML372 works

SMA is a neurodegenerative disease characterized by inadequate levels of a protein called survival motor neuron (SMN). The disease is caused by a mutation in the SMN1 gene that carries the instructions necessary to make SMN protein.

There is a second gene, SMN2, which also encodes for SMN protein. However, the protein produced from the SMN2 gene usually is smaller, unstable, and degrades easily. Only about 10% of the protein produced from the SMN2 gene functions correctly.

ML372 blocks the degradation of SMN2-generated SMN protein, making it more stable and increasing levels of the functional protein.

ML372 pre-clinical studies

ML372 has not yet been assessed in clinical trials. However, pre-clinical studies have shown some positive results, suggesting that ML372 may hold potential as a therapeutic candidate for treating SMA.

In cells cultured in the laboratory, ML372 was shown to prevent SMN degradation by blocking its ubiquitination by Mib1, which is the enzyme that ubiquitinates SMN. The ubiquitinproteasome pathway is one of the main pathways in our body that mediates protein degradation. Proteins are targeted for elimination based on the presence of a small molecule called ubiquitin. There are enzymes involved in the process of ubiquitination (the addition of ubiquitin marker on the proteins) that tags them for lysis (destruction).

The same study showed that treating fibroblast cells obtained from SMA patients with ML372 in the laboratory also resulted in an increase in SMN levels.

The researchers also evaluated the effectiveness of ML372 in a mouse model of SMA. One of the challenges of SMA therapeutic discovery is to identify molecules that can reach the nervous system (brain and spinal cord) to perform their function. In SMA mice, ML372 reached the nervous system when administered intraperitoneally (through the abdominal cavity).

Moreover, researchers detected significantly increased levels of SMN protein in the brain, spinal cord, and muscle tissues of the animals.

They reported that ML372  treatment improved weight gain in this mouse model. The animals also survived significantly longer compared to those in the placebo-treated group.

Finally, the research team assessed motor skills in their ML372-treated  mouse model by measuring their righting reflexes. Righting reflex is the ability of the mouse to flip over to a comfortable position when placed on its back. Muscle coordination is required for good righting reflexes. Assessment of motor function in ML372-treated SMA mouse indicated an improved ability to correct body orientation.


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