Experiences from treating seven adult 5q spinal muscular atrophy patients with Nusinersen

Abstract

Background: The antisense oligonucleotide Nusinersen recently became the first approved drug against spinal muscular atrophy (SMA). It was approved for all ages, albeit the clinical trials were conducted exclusively on children. Hence, clinical data on adults being treated with Nusinersen is scarce. In this case series, we report on drug application, organizational demands, and preliminary effects during the first 10 months of treatment with Nusinersen in seven adult patients. Methods: All patients received intrathecal injections with Nusinersen. In cases with severe spinal deformities, we performed computed tomography (CT)-guided applications. We conducted a total of 40 administrations of Nusinersen. We evaluated the patients with motor, pulmonary, and laboratory assessments, and tracked patient-reported outcome. Results: Intrathecal administration of Nusinersen was successful in most patients, even though access to the lumbar intrathecal space in adults with SMA is often challenging. No severe adverse events occurred. Six of the seven patients reported stabilization of motor function or reduction in symptom severity. The changes in the assessed scores did not reach a significant level within this short time period. Conclusions: Treating adult SMA patients with Nusinersen is feasible and most patients consider it beneficial. It demands a complex organizational and interdisciplinary effort. Due to the slowly decreasing motor functions in adult SMA patients, long observation phases for this recently approved treatment are needed to allow conclusions about effectiveness of Nusinersen in adults.

Muscle MRI in two SMA patients on nusinersen treatment: A two years follow-up

“…Recent studies have demonstrated the role of DTI in the detection and quantification of muscle fibers fat replacement [ 20 , Table 1 ]; FA is a parameter used to quantify the directional orientation of water molecules within the fibers; FA values are ranged between 0 and 1: in principle, when [ [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] ] tissues are intact, water is forced to move in a specific direction and the FA value is close to 1; unexpectedly patients with severe fat replacement show positive correlation with FA values and negative correlation with Apparent Diffusion Coefficient (ADC); a possible explanation is the artificial increase of FA values in patients with more than 40–45% fat muscle infiltration [ 25 ]. In our cases DTI showed that nusinersen treatment may have a positive effect on size, length and organization of fiber tracts raising the potential neurogenic rescue even in long-standing chronic SMA patients.…”

“…Spinal Muscular Atrophy (SMA) is an autosomal-recessive disorder caused by mutations in SMN1 gene, leading to degeneration of alpha motor neurons in the spinal cord resulting in progressive muscle weakness and disability [ [1] , [2] , [3] ]. The results from the pivotal [ 4 ] and more recent trials [ 5 ] with intrathecal nusinersen treatment, as well as the results from real world data [ 6 ], have created great expectations in older patients having long-lasting muscular atrophy and weakness; in fact there is growing evidence that treatment is at the very least stabilizing or providing some degree of improvement in motor function [ 7 ]. However, there are still some critical issues in understanding results in adults, including the lack of natural history data and outcome measures to monitor disease progression [ 8 ].…”

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

“…Nusinersen is administered via intrathecal injection, directly into the cerebrospinal fluid (CSF), in a two-phase treatment: (1) a loading phase of four doses 14, 14, and 30 days apart followed by (2) a maintenance phase with a dose every four months. Treatment with Nusinersen showed very promising results in young type 1 patients [ 14 , 15 ] and some positive effects in type 2 and 3 patients (no type 4 patients have been enrolled in clinical trials to date) [ 18 , 19 , 20 ]. Unexpectedly, the latter studies which include adult SMA patients (>18 years old) showed that their response to Nusinersen, evaluated as motor function improvement, was highly variable, with 40–50% of responders at best [ 18 , 19 , 20 ].…”

Clinical Variability in Spinal Muscular Atrophy Type III

“…It is, therefore, important to gather more information on the natural history of SMA type III for the interpretation of the realworld data that are increasingly becoming available. [19][20][21][22] The aim of this study was to describe the natural history in a large cohort of patients with SMA type III assessed longitudinally using the Hammersmith Functional Motor Scale Expanded (HFMSE). 23 More specifically, we were interested in establishing the distribution of scores at different ages, and the possible patterns of progression in patients with SMA types IIIA and IIIB.…”