{'fraction_non_alphanumeric': 0.02802332142185443, 'fraction_numerical': 0.02388564980252022, 'mean_word_length': 4.961883408071749, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 2, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Nusinersen: Evidence of sustained clinical improvement and lessened fatigue in older ambulatory patients with spinal muscular atrophy

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder resulting from biallelic mutations in the survival motor neuron 1 (SMN1) gene. Survival motor neuron protein is essential for the normal function and viability of motor neurons. An adjacent pseudogene, SMN2, differs from SMN1 by a single intronic mutation which causes its transcript to undergo alternative splicing and give rise to unstable pre-messenger ribonucleic acid (mRNA). Consequently, each SMN2 gene produces only about 10% of full-length, functional SMN protein. SMN2 copy number varies between individuals, and this copy number variability exerts a disease-modifying effect and gives rise to a spectrum of phenotypic severity. Severe, infantile-onset SMA (type I) is typically associated with two copies of SMN2. By comparison, children with type III SMA who exhibit symptom onset after 18 months of age and who show initially normal acquisition of ambulation most often have four copies of SMN2. Nusinersen is an antisense oligonucleotide that modifies the splicing of SMN2 pre-mRNA, resulting in increased production of SMN protein. Treatment with nusinersen has been shown to result in robust clinical improvement in presymptomatic and symptomatic children with infant-onset SMA. Natural history data have shown that untreated, infant-onset SMA is associated with a median age of survival or requirement for prolonged ventilator support (>16 hours/day) of 13.5 months. In a subsequent open-label study, early initiation of nusinersen (≤6 weeks old, presymptomatic infants) was associated with survival of all 25 infants without the requirement for permanent ventilation at a mean age of 26 months (range, 14.0–34.3). It is remarkable that, although 15 of 25 (60%) of the infants in this cohort had only two copies of SMN2 (predictive of SMA type I), all 25 achieved the ability to sit independently, and 22 (88%) developed the ability to walk with assistance. A subset of 17 of 22 (77%) infants that were >15.3 months old also achieved the ability to walk independently. An age of 15.3 months is the at which 95% of children in the general population begin walking independently. The attainment of such milestones in children with SMA type I is a dramatic shift from natural history data, which indicates that untreated children with two copies of SMN2would not have demonstrated sufficient strength to achieve head control or roll over. Nusinersen has also been shown to benefit a cohort of older (2–12 years old), symptomatic children with SMA, the majority (88%) of whom had three copies of SMN2 (predictive of SMA type II). After 15 months of treatment, the children who received nusinersen demonstrated a mean increase in Hammersmith Functional Motor Scale Extended (HFMSE) score of 4 points compared to the placebo group which demonstrated a mean loss of 1.9 points. Moreover, 13 of 84 (15%) patients in the treated group achieve at least one new World Health Organization motor milestone which was seen in two of 42 (5%) of the control group. On the basis of such promising results, nusinersen became the first treatment to be approved for SMA. As of August 2019, nusinersen has been approved in over 45 countries. Until recently, there has been little information available with regard to whether the effects of nusinersen are sustained or whether treatment efficacy is also seen in adolescents and adults with SMA. Long-term results from phase 1b/2a studies were recently published, confirming that benefit from nusinersen treatment for almost 3 years was associated with sustained improvement in motor function as well as stabilization of disease activity that is distinct from what is observed in natural history cohorts. In the October issue of Muscle & Nerve, Montes et al report important findings pertaining to the long-term effect of nusinersen treatment over almost 3 years in ambulatory patients (ages 2–15 years old) with SMA. Patients showed a progressive increase in the distance covered in the 6-minute walk test (6MWT), which, after 8 months, improved by a mean of 17 meters and, after 2.9 years, improved by a mean of 98 meters. The 6MWT is accepted as a reliable and valid outcome measure for ambulatory patients with SMA; an improvement in score such as that reported by Montes et al has not been observed in untreated patients with SMA. Fatigue was also recorded with long-term nusinersen treatment by subtracting the distance walked in the sixth minute of the 6MWT from the distance walked in the first minute of the test and expressed as a percentage. After a mean of 2.9 years of nusinersen treatment, fatigue did not worsen despite the increased walking distance. Fatigue-related changes are well described in patients with SMA; in one study, patients with SMA demonstrated a mean increased fatigue of 16.4% at baseline 6MWT and, when retested 1 month later, demonstrated a mean increased fatigue of 20.3%. The observation that fatigue did not worsen with prolonged nusinersen treatment provides encouraging evidence that this therapy offers sustained benefit to older patients with SMA. Received: 9 September 2019 Revised: 30 September 2019 Accepted: 2 October 2019