CHOP INTEND Research Articles

Administration of gene replacement therapy in patients with spinal muscular atrophy 5q type 1 with chronic nosocomial bronchopulmonary infection

Introduction. Spinal muscular atrophy (SMA) 5q is a severe hereditary neuromuscular disorder, one of the serious manifestations of which is the development of progressive respiratory insufficiency. The administration of pathogenetic therapy leads to decreased symptoms of respiratory failure, which reduces the risk of lethal outcome and is fundamental for stabilizing the progression of physical development and new motor skills in SMA patients. The aim — to present experience of onasmenogen abeparvovec (OA) gene replacement therapy (GRT) in patients with SMA type 1 and severe respiratory failure combined with chronic bronchopulmonary infection caused by nosocomial multidrug-resistant microflora in real clinical practice. Materials and methods. Five patients with SMA type 1 and respiratory failure of second degree complicated by chronic bronchopulmonary infection were enrolled in this study. All patients were performed a comprehensive clinical, laboratory, and radiologic examination before and for two years after GRT OA administration toof evaluate the severity of respiratory disturbances. The efficiency of OA therapy was estimated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), and motor development was assessed by the Hammersmith Infant Neurologic Examination Part 2 (HINE-2). Results. The medical records of 5 (four boys and one girl ) patients with SMA type 1 at the mean age of 19 months (13 to 27 months) at the time of GRT OA administration were analyzed, of them. All patients had been treated with a different type of pathogenetic therapy before GRT OA. After the preventive, personalized antibacterial therapy, all patients experienced GRT OA administration without exacerbation of chronic bronchopulmonary infection, despite hormonal therapy in an immunosuppressive dose (1 mg/kg). There were no lethal outcomes during two years after GRT OA. Over the first year, patients demonstrated a progressive increase in motor skills with further stabilization, but during the second year of follow-up, two patients showed moderate regression of motor skills after pneumonia. One of five patients had a positive lung function dynamics and eradication of highly pathogenic bacterial microflora from the respiratory tract. Conclusions. It is comparatively safe to administer GRT OA in children with SMA type 1 and chronic respiratory infection. However, changing pathogenetic therapy to GRT OA in the cases we presented did not have clinically significant advantages and required more careful patient preparation. Additional risks associated with the occurrence of immune-mediated adverse events due to concomitant hormonal therapy, which can be avoided on other types of pathogenetic therapy, should be considered.

Type 1 spinal muscular atrophy treated with nusinersen in Norway, a five-year follow-up

BackgroundNew treatments for 5q spinal muscular atrophy (SMA) have led to changes in the disease phenotype. Questions about long-term efficacy, however, persist. We present the results from five-year follow-up of the first ten Norwegian patients with SMA type1 treated with nusinersen. Methods– Ten patients referred to the expanded access program were included. Standardized assessments with Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), the Hammersmith Infant Neurological Examination (HINE-2), compound muscle action potential (CMAP) examination and cerebrospinal fluid analysis of neurofilament light chain (cNfL) were performed. ResultAge at baseline ranged from three months to 11 years and eight months. Nine patients were alive and continued to receive treatment at 62 months of follow-up. CHOP INTEND scores increased significantly up to 38 months. Any further increase from 38 to 50 months was not statistically significant, and scores remained almost unchanged from 50 to 62 months. HINE-2 scores increased but the difference from baseline never reached statistical significance.The youngest patients showed the best motor outcome. The changes in CMAP scores were not statistically significant. cNfL values were significantly reduced after 18 months compared with baseline; the largest difference occurred between baseline and 6 months. There was a significant negative correlation between log cNfL and CHOP INTEND (p = 0.042). Bulbar and respiratory function did not improve during the observation period. ConclusionOur findings support previously reported results on efficacy and safety of nusinersen. All patients have shown improvement in motor function. The need of respiratory and nutritional support did not improve.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

Prognostic factors for tube feeding in type I SMA patients treated with disease-modifying therapies: a cohort study

The aim of this study was to assess the need for tube feeding in a cohort of treated infants with type I SMA and to identify predictive factors. All patients were classified at baseline, when treatment started, and at follow-up according to their functional level and the need for tube feeding. Fisher’s exact test was used to examine the associations between the outcome at the last follow-up and SMA type, SMN2 copy number, and baseline nutritional status. ANOVA was performed to compare CHOP INTEND scores and age at treatment initiation with outcomes. The cohort includes 75 type I SMA infants treated between 0.1 and 5 years of age. At the last follow-up, 34 had no need for tube feeding, 9 had tube feeding but were also able to be fed by mouth, and 32 had tube feeding and were unable to be fed by mouth. Thirty of the 41 infants with tube feeding at follow-up already had feeding difficulties when treatment was started. The need for tube feeding at follow-up was associated with the level of feeding involvement at baseline and with CHOP INTEND scores [p < 0.001] but not with SMN2 copy number, SMA type 1 subtypes or age at treatment. The results of this study suggest that the need for tube feeding is not frequent in treated infants with type I SMA and, when occurring, can be predicted by the level of feeding involvement and low CHOP INTEND scores at baseline.What is Known:• The advent of disease-modifying therapies is increasingly changing the approach to swallowing and nutritional management in type I SMA.• Clinical trials and real-world data using all three disease-modifying therapies report a rather wide variability of feeding outcome and need for tube feeding that is often related to different cohorts that makes comparison between studies very difficult.What is New:• The real-world findings of this study, including all the children treated since treatments became available, confirmed that the need for tube feeding is not an invariable finding.• The level of feeding involvement at baseline appears to be a reliable prognostic indicator of bulbar outcome.• The results highlight the need for interventional studies with structured Speech and Language Therapist protocols that will help to better understand the extent to which bulbar function can be maintained or regained even in children requiring tube feeding.

Improvement in functional motor scores in patients with non-ambulatory spinal muscle atrophy during Nusinersen treatment in South Korea: a single center study

We analyzed the changes in various motor function scores over a four-year period in patients with non-ambulatory spinal muscular atrophy (SMA) during Nusinersen treatment. Patients underwent Hammersmith Infant Neurological Examination (HINE) or Hammersmith Functional Motor Scale Expanded (HFMSE) before treatment, and approximately every 4 months thereafter. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) or Children’s Hospital of Philadelphia – Adult Test of Neuromuscular Disorders (CHOP ATEND), Revised Upper Limb Module (RULM), and Motor Function Measure (MFM) were performed based on baseline functional status. Narrative interviews were conducted to explore post-treatment physical improvement regarding activities of daily living (ADLs) and fatigue after ADLs. Based on HFMSE results, 9 patients achieved minimum clinically important differences. Average rates of change (slopes) with corresponding 95% confidence intervals for all assessment tools were in a positive direction. CHOP-INTEND showed the most prominent improvement in children and adolescents followed by HFMSE. Improvements in CHOP-ATEND were most noticeable in adults. Improvements were accompanied by changes in ADLs as observed in the narrative interviews. It is necessary to consider various functional aspects to determine the effectiveness of Nusinersen therapy. The objective assessment of the therapeutic effect of Nusinersen in non-ambulatory SMA requires consideration of functional aspects and the related ADLs.

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.

Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.

Gene therapy for spinal muscular atrophy (SMA): First experience with Onasemnogene abeparvovec (Zolgensma®) in a private hospital in Mexico

Spinal muscular atrophy is a hereditary neuromuscular disease characterized by the degeneration of alpha motor neurons of the anterior horn of the spinal cord, leading to progressive symmetrical muscle weakness and a high risk for respiratory complications resulting in the need for some degree of ventilatory support. Two infants are presented with hypotonic syndrome in which spinal muscular atrophy was diagnosed by a genetic study. Gene therapy with Zolgensma® was used to evaluate the clinical improvement in motor function according to the Chop Intend Scale.

Switching from Nusinersen to Risdiplam: A Croatian Real-World Experience on Effectiveness and Safety.

(1) Background: Data on combination or sequential treatment of spinal muscular atrophy (SMA) with disease-modifying drugs (DMDs) are missing and the latter field is poorly understood. The currently available data of patients on risdiplam previously treated with nusinersen are coming from exploratory research mainly focused on safety. Our aim was to investigate the real-world effectiveness (hypothesising non-inferiority) and safety profile of risdiplam in a paediatric-and-adult nusinersen-risdiplam spinal muscular atrophy switch cohort. (2) Methods: A retrospective and anonymous collection of relevant demographic and clinical data for all Croatian SMA patients switched from nusinersen to risdiplam up to September 2023 (reimbursed by Croatian Health Insurance Fund-CHIF) was performed using the CHIF database and associated reimbursement documentation. Patients were included in effectiveness and safety analysis if they met the following inclusion criteria: (i) risdiplam was reimbursed by the CHIF; (ii) the patient received at least six doses of nusinersen before the switch to risdiplam; (iii) there was no relevant pause between the latter disease-modifying drugs; (iv) availability of all prespecified studied data and parameters. (3) Results: In total, 17 patients met the inclusion criteria (58.9% female; median age 12.75 (3.0-44.5) years). In our 'switch' cohort, we demonstrated a non-inferiority of risdiplam to nusinersen in the SMA 1 (+1.0 in CHOP INTEND; p = 0.067), SMA 3p (+0.7 in HFMSE; p = 0.897), and SMA 3a (+0.8 in RHS; p = 0.463) subpopulations, during a one-year follow-up period. There were no reports on respiratory function worsening, feeding worsening, and no lethal events. No new safety concerns were identified, except for the weight gain that arose as a new potential adverse drug reaction 'signal' in two patients. (4) Conclusions: We have reported pivotal real-world findings on switching SMA patients from nusinersen to risdiplam and demonstrated its effectiveness (non-inferiority), safety, and tolerability in a heterogenous paediatric-and-adult 'switch' cohort; this will further increase the quality and standards of care as well as safety of a notable portion of SMA patients, especially for those who demand the switch from nusinersen to other DMDs for clinical or personal reasons.

Role of the Physical Therapy Intervention in Type 1 Spinal Muscle Atrophy: A Case Study

Background: Spinal Muscle Atrophy Type 1 (SMA1) is a hereditary neuromuscular disorder that affects the motor neuron, leading to sever muscles weakness and limited motor function. Zolgensma therapy has emerged as potential treatment option for SMA1, offering hope for improved outcomes and quality of life for affected infants. However, the effectiveness of the therapy in promoting physical development in SMA1 remains unclear1. This case study aim to explore the role of physiotherapy in improving the developmental milestones of an infant with SMA1 following gene therapy. Additionally, will utilize the Chop Intend assessment tool to assess and track the changes in infant’s motor function, strength, and over all physical development. Case discerption: 7 weeks new borne girl referred from neurology department to physical rehabilitation department, with history of SMA1. Management and outcomes: The baby was seen twice/week, assessed by CHOP-INTEND assessment tool and followed by active ROM exercises, stretching exercises and Neuro-developmental therapy for the last two years. Outcomes was measures by CHOPINTEND assessment, which improved from 45 to 64. Result: This study highlights the significant benefits of physiotherapy in improving motor milestones in patients with SMA1.

Evaluation of risdiplam efficacy in 5q spinal muscular atrophy: A systematic comparison of electrophysiologic with clinical outcome measures.

To assess compound muscle action potential (CMAP) amplitudes as electrophysiologic markers in relation to clinical outcome in adult patients with 5q-linked spinal muscular atrophy (SMA) before and during treatment with risdiplam. In this monocentric longitudinal cohort study, CMAP of 18 adult patients with SMA type 2 or 3 were assessed at baseline (T0 ) and after 10 months (T10 ) of risdiplam treatment. CMAP amplitudes of the median, ulnar, peroneal, and tibial nerves were compared with established clinical outcome scores, and with the course of disease before start of treatment. During a pharmacotherapy-naive pre-treatment period of 328 ± 46 days, Revised Upper Limb Module (RULM) score and peroneal nerve CMAP amplitudes decreased, while CMAP of tibial and upper limb nerves remained unchanged. CMAP amplitudes positively correlated with clinical scores (Hammersmith Functional Motor Scale-Expanded [HFMSE], RULM) at T0 . During risdiplam treatment, HFMSE and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores increased, paralleled by marked increase of CMAP amplitudes in both median nerves (T10 -T0 ; right: Δ = 1.4 ± 1.4 mV, p = 0.0003; left: Δ = 1.3 ± 1.4 mV, p = 0.0007), but not in ulnar, peroneal, or tibial nerves. A robust increase of median nerve CMAP amplitudes correlated well with an increase in the HFMSE score (T10 -T0 ). Median nerve CMAP amplitudes at T0 were associated with subsequent risdiplam-related improvement of HFMSE and CHOP INTEND scores at T10 . Median nerve CMAP amplitudes increase with risdiplam treatment in adult SMA patients, and should be further evaluated as potential easy-to-use electrophysiologic markers in assessing and monitoring clinical response to therapy.

Brazilian version of the CHOP INTEND scale: cross-cultural adaptation and validation.

Spinal muscular atrophy (SMA) is a rare genetic disease that causes progressive muscle weakness and impacts motor function. The type I is the most severe presentation and affects infants before 6 months old. In addition, the instruments available for assessing motor function have limitations when applied to infants with neuromuscular diseases and significant muscle weakness. To translate, cross-culturally adapt, and validate the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) to Brazilian Portuguese. The present study comprised the translation, synthesis of translations, backtranslation, consolidation by a committee of experts, and test of the final version of the CHOP INTEND in 13 patients with SMA type I. We also assessed the content validity and reliability of the translated version. The scale was translated considering semantic, structural, idiomatic, and cultural aspects. All agreement rates were > 0.8, the overall content validity index of the instrument was 0.98, and inter-rater reliability using the intraclass correlation coefficient was 0.998. The Brazilian version of the CHOP INTEND met semantic and technical equivalence criteria with the original version and was valid and reliable for patients with SMA type I.

Registry of Patients with Spinal Muscular Atrophy in a Tertiary Care Unit in Egypt

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Objectives To register patients with SMA who are diagnosed clinically and genetically (typical and atypical forms) in a tertiary care unit in Egypt. Patient and methods 80 Patients with SMA who are diagnosed clinically and genetically at Neuromuscular Unit of Ain Shams University Hospital were registered. Demographical data and genetics of the patients were collected and analyzed. The patients were assessed for skeletal deformities, cardiac evaluation by echo and pulmonary evaluation by PFTs (for patients above 5 years old) and functional assessment by motor scales according to age and type of each patient was done. Results SMA was more common in males with predominance of type II and median age of 4.5 years old, a considerable number of cases had positive history of consanguinity and similar cases in family, 98.8% of cases had the typical form of SMA with homozygous deletion of SMN1 gene with variable SMN2 copy number according to type. 32.5% of cases had skeletal deformities in the form of scoliosis with or without kyphosis, extremities contractures and chest cave deformities. 4 cases had restrictive pattern due to scoliosis cardiac abnormalities were detected in 3 cases of type I. 31 cases were assessed by CHOP INTEND and 49 cases were assessed by HFMSE giving a good tool for assessing disease progress and role of physiotherapy. Severe chest infection and respiratory failure was the cause of death of 3 cases of type I during the period of study. Conclusion registry of SMA patients will lead to a better understanding of the natural history of SMA and the influence of drug treatment. This is crucial to improve the care of SMA patients.

Long-term nusinersen treatment across a wide spectrum of spinal muscular atrophy severity: a real-world experience

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a biallelic mutation in the SMN1 gene, resulting in progressive muscle weakness and atrophy. Nusinersen is the first disease-modifying drug for all SMA types. We report on effectiveness and safety data from 120 adults and older children with SMA types 1c-3 treated with nusinersen.MethodsPatients were evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE; n = 73) or the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; n = 47). Additionally, the Revised Upper Limb Module (RULM) and 6-minute walk test (6MWT) were used in a subset of patients. Patients were followed for up to 30 months of nusinersen treatment (mean, SD; 23, 14 months). Subjective treatment outcomes were evaluated with the Patients Global Impression–Improvement (PGI-I) scale used in all patients or caregivers at each follow-up visit.ResultsAn increase in the mean HFMSE score was noted at month 14 (T14) (3.9 points, p < 0.001) and month 30 (T30) (5.1 points, p < 0.001). The mean RULM score increased by 0.79 points at T14 (p = 0.001) and 1.96 points (p < 0.001) at month 30 (T30). The mean CHOP-INTEND increased by 3.6 points at T14 (p < 0.001) and 5.6 points at month 26 (p < 0.001). The mean 6MWT improved by 16.6 m at T14 and 27 m at T30 vs. baseline. A clinically meaningful improvement in HFMSE (≥ 3 points) was seen in 62% of patients at T14, and in 71% at T30; in CHOP INTEND (≥ 4 points), in 58% of patients at T14 and in 80% at T30; in RULM (≥ 2 points), in 26.6% of patients at T14 and in 43.5% at T30; and in 6MWT (≥ 30-meter increase), in 26% of patients at T14 and in 50% at T30. Improved PGI-I scores were reported for 75% of patients at T14 and 85% at T30; none of the patients reporting worsening at T30. Adverse events were mild and related to lumbar puncture.ConclusionsIn our study, nusinersen led to continuous functional improvement over 30-month follow-up and was well tolerated by adults and older children with a wide spectrum of SMA severity.

Treatments and Outcomes for Patients with Spinal Muscular Atrophy Type 2: Findings from RESTORE Registry (P7-9.010)

Treatments and Outcomes for Patients with Spinal Muscular Atrophy Type 2: Findings from RESTORE Registry (P7-9.010)

Outcomes in Patients with Spinal Muscular Atrophy and Four or More SMN2 Copies Treated with Onasemnogene Abeparvovec: Findings from RESTORE (P7-9.007)

Outcomes in Patients with Spinal Muscular Atrophy and Four or More SMN2 Copies Treated with Onasemnogene Abeparvovec: Findings from RESTORE (P7-9.007)

Effectiveness of Nusinersen in Type 1, 2 and 3 Spinal Muscular Atrophy: Croatian Real-World Data.

(1) Background: To investigate the real-world effectiveness and safety profile of nusinersen in Croatian paediatric and adult spinal muscular atrophy (SMA) patients. (2) Methods: A retrospective and anonymous collection of relevant demographic and clinical data for all Croatian SMA patients treated with nusinersen and reimbursed by the Croatian Health Insurance Fund (CHIF) between April 2018 and February 2022 was performed through searching the CHIF database and studying the associated reimbursement documentation. All patients who received at least one dose of nusinersen were included in the baseline clinical-demographic overview and safety analysis, whereas only subjects who had completed six doses were included in the effectiveness analysis. (3) Results: Fifty-two patients [61.5% male; median age 13.4 (0.1-51.1) yr.] received nusinersen treatment. In SMA type 1 and type 3 paediatric patients, statistically significant motor function improvement (CHOP INTEND 10.8 ± 10.3 vs. 20.0 ± 15.8, p = 0.003; HFMSE 49.6 ± 7.9 vs. 53.1 ± 7.7, p = 0.008; respectively) was achieved immediately after 4 loading doses of nusinersen and remained statistically significant onwards. Average improvements in HFMSE motor performance in SMA type 2 patients after four, five, and six doses of nusinersen were +6.0, +10.5, and +11.0 points, respectively. In SMA type 3 adult patients, no significant improvement in RHS motor performance or the 6-Minute Walk Test (MWT) was demonstrated. During the study period, 437 doses were administered without any new safety concerns appearing. (4) Conclusions: Our RWD findings indicate that nusinersen is an effective and safe treatment in a heterogeneous group of paediatric patients with all types of SMA; however, no significant benefit (but only RHS and 6MWT maintenance) was demonstrated in SMA type 3 patients who started nusinersen after >18 years of age.

Type I Spinal Muscular Atrophy patients treated with nusinersen: 4 year follow-up of motor, respiratory and bulbar function.

We report the 4 year follow up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-2). Forty-eight patients, with age ranging from 7 days and 12 years (mean 3.3, SD 3.6) were included in the study. The CHOP INTEND and HINE-II score significantly increased between baseline and 48 months (p<0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, >12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.

Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study

BackgroundSpinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland.MethodsProspective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed.ResultsNine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter.ConclusionsOA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

Safety and efficacy of gene therapy with onasemnogene abeparvovec in the treatment of spinal muscular atrophy: A systematic review and meta-analysis.

Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease which leads to progressive muscle weakness and atrophy. Our systematic review and meta-analysis aims to explore the efficacy and safety of onasemnogene abeparvovec in SMA patients. We searched PubMed, EMBASE, Web of Science and Cochrane through April 2022. Ten reports enrolling 250 SMA patients were included. CHOP INTEND and motor-milestone significant improvements were detected at both short- and long-term follow-up. Common adverse events included pyrexia, vomiting, thrombocytopenia and elevated aminotransferases. Thrombocytopenia (79.3%, 95%CI: 65.8~90.5) and elevated aminotransferases (71.7%, 95%CI: 62.5~80.1) were more common in SMA patients aged older than 8 months. Despite the paucity of randomized control trial data and low quality of evidence to establish the safety and efficacy of onasemnogene abeparvovec in the treatment of SMA, the data suggest that it is a valuable option for patients with this condition.

Interim Analysis of Treatment Outcomes of Young Children with 5q Spinal Muscular Atrophy on Gene Replacement Therapy with Onasemnogene Abeparvovec. Clinical Observations

Background. Onasemnogene abeparvovec is the first gene replacement therapy medication based on the adeno-associated viral vector (AAV9). One injection to a patient with 5q spinal muscular atrophy (SMA) leads to replacement of the missing or defective SMN1 gene with its functional copy. It leads to normalization of survival motor neuron protein (SMN) production.Objective. The aim of the study is to evaluate efficacy, safety, and causes of different responses to therapy after single administration of onasemnogene abeparvovec in 5 patients with 5q SMA (types I and II) comparing the baseline status with the results of continued monitoring in real clinical practice in Russian Federation.Methods. Interim results of continued follow-up of children with 5q SMA with 2–3 copies of the SMN2 gene are presented: 2 boys and 1 girl with type I who received single dose of onasemnogene abeparvovec at 4 and 7 months of age; and 2 girls with type II who received therapy at 11 and 16 months of age.Results. Short-term controlled fever was observed in 4 out of 5 patients during first 2 weeks after viral vector therapy administration (max in patient 5 — up to 38.5 ° C). All 5 children had transaminases increase, 1 patient — significant transaminases increase during the sensitisation period (&gt; 10 from upper normal level (UNL)), 1 patient — delayed significant transaminases increase (&gt; 20 UNL), 1 patient — transaminases increase (&gt; 3 UNL) after discontinuation of longterm therapy with glucocorticosteroids (according to prescribing information). All patients had shown positive and sustained response to therapy over time at motor status assessment via CHOP INTEND / HFMSE scales. The more significant response was observed in patients with less aggressive baseline 5q SMA type II with 3 copies of the SMN2 gene.Conclusion. Onasemnogene abeparvovec is relatively safe medication for management of children with 5q SMA. Thus, the development of adverse events and their mechanisms should be further studied, as well as long-term follow-up of recipients is required to gather knowledge on this medication effects on human body.