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      Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

      1 , 2 , 1 , 2 , 3

      Developmental Medicine & Child Neurology

      Wiley

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          Abstract

          Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.

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          Most cited references 10

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          An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN.

          The survival motor neuron genes, SMN1 and SMN2, encode identical proteins; however, only homo- zygous loss of SMN1 correlates with the development of spinal muscular atrophy (SMA). We have previously shown that a single non-polymorphic nucleotide difference in SMN exon 7 dramatically affects SMN mRNA processing. SMN1 primarily produces a full-length RNA whereas SMN2 expresses dramatically reduced full-length RNA and abundant levels of an aberrantly spliced transcript lacking exon 7. The importance of proper exon 7 processing has been underscored by the identification of several mutations within splice sites adjacent to exon 7. Here we show that an AG-rich exonic splice enhancer (ESE) in the center of SMN exon 7 is required for inclusion of exon 7. This region functioned as an ESE in a heterologous context, supporting efficient in vitro splicing of the Drosophila double-sex gene. Finally, the protein encoded by the exon-skipping event, Delta7, was less stable than full-length SMN, providing additional evidence of why SMN2 fails to compensate for the loss of SMN1 and leads to the development of SMA.
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            Disease burden of spinal muscular atrophy in Germany

            Background This study aimed at analyzing the economic burden and disease-specific health-related quality of life (HRQOL) of patients with spinal muscular atrophy (SMA) in Germany. SMA is a so far non-curable neuromuscular disease of the anterior nerve cells that causes high rates of morbidity and mortality. Methods In a cross-sectional study we analyzed the cost of illness (COI) and factors that influence the direct, indirect and informal care costs of affected patients and their families by using standardized, self-developed questionnaires. We used the PedsQL™© Measurement Model to analyze the disease-specific HRQOL of patients. Results One hundred eighty nine patients with SMA types I to III aged <1 to 73 years were enrolled. The average annual COI was estimated at €70,566 per patient in 2013. The highest cost resulted in SMA I with significant lower costs for the milder phenotypes. Inversely, the self-estimated HRQOL increased from SMA I to SMA III. Major cost drivers were informal care cost and indirect cost incurred by patients and their caregivers. Conclusions Although SMA requires high standards of care, there has been a distinct lack of health services research on SMA. Accordingly, our results significantly contribute to a more comprehensive insight into the current burden of SMA and quality of life status as related to SMA health services in Germany. In the light of innovative therapeutic interventions, our results suggest a notable potential for a reduction in overall COI and improvement of HRQOL if the therapeutic intervention leads to a less severe course of the disease.
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              Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study

              To evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1). Patients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109 ). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32). We treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment ( p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 ( SMN2 ) gene. Our results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease. NCT02865109. This study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.
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                Author and article information

                Journal
                Developmental Medicine & Child Neurology
                Dev Med Child Neurol
                Wiley
                0012-1622
                1469-8749
                July 29 2018
                January 2019
                September 17 2018
                January 2019
                : 61
                : 1
                : 19-24
                Affiliations
                [1 ]I‐Motion – Pediatric Clinical Trials Department Trousseau Hospital Paris France
                [2 ]Institute of Myology Pitié‐Salpêtrière Hospital Paris France
                [3 ]CHU de Liège Centre de référence des maladies Neuromusculaires Liège Belgium
                Article
                10.1111/dmcn.14027
                30221755
                © 2019

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