Spinal muscular atrophy: mechanisms and therapeutic strategies

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and a leading genetic cause of infantile mortality. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The clinical features of the disease are caused by specific degeneration of alpha-motor neurons in the spinal cord, leading to muscle weakness, atrophy and, in the majority of cases, premature death. A highly homologous copy gene (SMN2) is retained in almost all SMA patients but fails to generate adequate levels of SMN protein due to its defective splicing pattern. The severity of the SMA phenotype is inversely correlated with SMN2 copy number and the level of full-length SMN protein produced by SMN2 ( approximately 10-15% compared with SMN1). The natural history of SMA has been altered over the past several decades, primarily through supportive care measures, but an effective treatment does not presently exist. However, the common genetic etiology and recent progress in pre-clinical models suggest that SMA is well-suited for the development of therapeutic regimens. We summarize recent advances in translational research that hold promise for the progression towards clinical trials.

Parental attitudes toward newborn screening for Duchenne/Becker muscular dystrophy and spinal muscular atrophy

“…Most often, SMA refers to the most common disease in this groupproximal SMA -which is further subdivided into four types based on clinical severity, as described in detail below (Engel, 2004;Wee, 2010). The incidence of SMA is between 1 in 6000 and 1 in 10,000 births (Su, 2011;Lorson, 2010;Pearn, 1978), making it the most common fatal autosomal recessive disorder (Prior, 2010).…”

“…It is thought that this silent change either disrupts an exonic splicing enhancer (ESE) or creates an exonic splicing silencer (ESS) (Kashima, 2003;Lorson, 2010). Although the exact mechanism is not known, SMN2 is known to primarily produce a quickly-degraded RNA product lacking exon 7, called SMN∆7, although some amount of functional SMN protein is also produced (Lorson, 2010). SMA prognosis is correlated with the amount of SMN protein preserved.…”

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

“…5 A therapy leading to reliable upregulation of SMN2 transcription can therefore be expected to be effective in most SMA patients. Hence, many therapeutic strategies have been suggested and reported, including: (i) elevation of SMN2 RNA and protein levels by transcription activation, correction of SMN2 splicing or stabilization of protein using drugs or antisense oligos, (ii) gene replacement by gene therapy approaches, (iii) neuroprotective therapy and (iv) stem cell therapy (reviewed in [15][16][17]18 ). Despite these promising experimental approaches, no readily available effective treatment for SMA exists to date.…”

Spinal muscular atrophy counteracted by Agrin biological NT-1654

“…Among the two almost identical SMN (survival motor neuron) genes that are present on chromosome 5q13. SMA1 is only affected while SMN2 gene is not affected by the disease [3]. On the basis of age of onset and disease severity, SMA can be classi ied into four main clinical types (I-IV from severe to mild) [4].…”

“…According to the severity of the malady. It is represented by MN degeneration resulting in the affected patient's muscular atrophy, paralysis and lessened lifespan, [3]. The SMN complex, is built of the SMN protein and 7 additional proteins (Gemin2-8), which plays a pivotal role in the assembly and biogenesis of snRNPs, and in pre-mRNA splicing.…”