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May 7, 2018 News by Marta Figueiredo, PhD

Small Molecules Show Potential to Treat SMA by Raising SMN Protein Levels, Study Says

Researchers have unraveled the cellular mechanisms behind two RG7916-like splicing modifiers that increase the levels of SMN — the protein missing in spinal muscular atrophy — and suggest these small molecules may indeed lead to treatments of benefit to patients. SMA is caused by mutations in the SMN1 gene, which leads to a reduction in the load of survival motor neuron protein.  A second survival motor neuron gene, SMN2, with an identical sequence, can ease the damage done by the mutation but only to a very limited degree. SMN2, like SMN1, is capable of producing SMN. But a slight difference in its DNA sequence leads to an event called alternative splicing (editing) of a premature version of its messenger RNA — the molecule that guides protein production. This difference causes 90 percent of its resulting SMN protein to be shorter and nonfunctional. Several approaches that therapeutically target alternative splicing of SMN2 are currently in various stages of development. These range from an approved antisense oligonucleotide — Spinraza — to small molecules shown to promote the correct splicing of SMN2 mRNA and to increase levels of a functional SMN protein. RG7916 is one of those small molecules, now in three Phase 2 or Phase 2/3 clinical trials for several types of SMA (FIREFISH, SUNFISH, and JEWELFISH). It is an oral treatment intended to bypass the blood-brain barrier and effectively reach the central nervous system, the brain and spinal cord. Latest data from the SUNFISH and JEWELFISH studies showed that RG7916 increases the protein levels of SMN. An additional study in a SMA mouse model found that molecules structurally similar to RG7916 that can modify SMN2 splicing also induce a comparable increase in SMN protein in the animals' blood and brain. Two small molecules structurally similar to RG7916 — called SMN-C2 and SMN-C3 — were found to promote the correct splicing of SMN2, presumably through mechanisms similar to RG7916. Researchers, looking to better understand the mechanisms behind these molecules and potentially help with the design of future splicing modulators, performed a series of chemical and genetic studies. SMN-C2 and SMN-C3 were found to directly bind to SMN2 pre-mRNA, inducing conformational changes that increase the binding of two proteins involved in pre-mRNA splicing, FUBP1 and KHSRP. This binding was shown to increase the correct splicing of SMN2. “These findings underscore the potential of small-molecule drugs to selectively bind RNA and modulate pre-mRNA splicing as an approach to the treatment of human disease,” the researchers wrote.

May 4, 2018 News by Ashraf Malhas

Canadian Researchers Receive Funding to Develop New Test to Track SMA Progression

Researchers at The Ottawa Hospital in Canada have received $150,000 from Cure SMA to develop new ways of monitoring spinal muscular atrophy (SMA) using a noninvasive blood test. The team, led by Robin Parks, PhD, intends to use tiny bits of cells called exosomes to develop ways of tracking SMA progression and how patients respond to treatment. Parks is a senior scientist in the regenerative medicine program at Ottawa Hospital Research Institute and the director of PhD research in the department of medicine at The Ottawa Hospital, as well as a professor at the University of Ottawa. SMA occurs in about 1 in 10,000 live births and is considered the most common cause of death by a genetic disease in newborns. It's caused by a deficiency of a protein known as the SMN protein. Several experimental therapies are currently under investigation for the treatment of SMA. And Spinraza (nusinersen), a medication that acts by increasing the body's ability to produce SMN proteins, has already been approved by the United States Food and Drug Administration, Health Canada, and the European Union for the disease. Research suggests that the earlier a treatment is delivered, the more effective it will be. However, there is not yet a test that can measure how a patient is responding to these therapies, a particularly difficult task in young babies, which Parks and his team are hoping to address. Exosomes are small vesicles (about 30-100 nanometers in diameter) released by cells, which can serve several purposes, including cell-to-cell communication. Since exosomes can spread and distribute various molecules among cells, they have been implicated in the development of diseases, including SMA. A previous study by Parks' team, published in Scientific Reports, revealed that the levels of SMN proteins in exosomes found in the blood were lower in both an SMA mouse model and an SMA type 3 patient, compared with healthy controls. Results of this study indicate that SMN levels in exosomes could be used as a biomarker for SMA progression. The new research, which builds on this previous work, will be conducted in collaboration with Children's Hospital of Eastern Ontario (CHEO) and the University of Missouri.

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