Author Archives: Marta Figueiredo PhD

Walking Ability in Type 3 SMA Declines Significantly in Adolescence, Study Finds

Walking ability in type 3 SMA patients is significantly impaired during adolescence, according to recent research. Type 3 SMA, also known as Kugelberg-Welander disease, is a milder form of SMA. Muscle weakness in type 3 SMA mainly affects patients’ limb movements, and children are generally able to stand and walk. These abilities decrease over time, however. Symptoms usually appear between 18 months and early teens. Symptom onset before age 3 is classified as type 3A SMA, and onset at later ages as type 3B — considered a milder SMA subtype. However, while SMA is thought to be a largely stable disorder, recent studies have highlighted different rates of progression based on age and function. In patients who cannot walk, gross motor function improves until about age 5, then worsens until about age 15, followed by a relatively stable phase in late adolescence and adulthood. While ambulatory patients have a similar disease progression to that of non-ambulatory patients, a more specific assessment may be necessary to identify changes in walking function. Researchers used data from three prospective natural history studies to evaluate changes in walking ability in 73 individuals with type 3 SMA who were able to walk without support for at least 10 meters. The team used the  the six-minute walk test, a valid and reliable functional assessment that measures the distance a person can walk in six minutes. While the 6MWT was initially developed to evaluate functional exercise capacity in heart- and lung-associated diseases, it has become a valuable and reliable test to measure functional walking ability in SMA patients. The study showed that the ability to walk strongly deteriorated during adolescence with a loss of 20.8 meters per year, and slowly declined again through adulthood with a loss of 9.7 meters per year. The age around puberty appeared to be the most vulnerable period in ambulant patients, with researchers hypothesizing that weight gain and growth associated with puberty could contribute toward a greater decline in walking capacity. The study authors emphasized that when designing future clinical trials with SMA patients, it is important to understand the natural history of the disease and identify disease trajectories as measured by the 6MWT to better interpret patients' response to treatment.

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.

#AAN2018 — Spinraza Improves Motor and Respiratory Function in SMA Children, Trials Show

Spinraza (nusinersen) improves motor and respiratory function in children with spinal muscular atrophy (SMA), according to results from different trials. Biogen will present the data at the American Academy of Neurology annual meeting, taking place April 21-27 in Los Angeles. SMA is a neurodegenerative disease caused by mutations in the SMN1 gene, which provides…