Type-1 spinal muscular atrophy cohort before and after disease-modifying therapies

Abstract

Background Spinal muscular atrophy (SMA-5q) is a neurodegenerative disease characterized by progressive muscle atrophy, hypotonia, and weakness, with SMA 1 presenting symptoms within the first 6 months of life. Disease-modifying therapies have been approved, with better outcomes with earlier treatment.

Objective To describe the safety and clinical efficacy of disease-modifying therapies based on SMN1 and SMN2 gene strategies concerning motor, respiratory, and bulbar function. Patients with SMA 1 were divided into 2 groups: those exclusively on nusinersen (group 1) and those transitioning to onasemnogene abeparvovec (OA) (group 2).

Methods Over 18 months, patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale, developmental milestones, ventilation needs and duration, nutritional support needs, consistency of food, and signs of dysphagia. There were ten patients, divided between the groups; in group 1, the average age for starting nusinersen was 53.6 (12–115) months, and, in group 2, the age was 7 (1–12) months for nusinersen and 15.2 (10–19) months for OA.

Results Our results indicate that 70% of patients reached some motor milestones, with group 1 increasing by 10.2 points on the CHOP-INTEND scale, while group 2 increased by 33 points. Additionally, 90% of the patients experienced no respiratory decline, and 30% maintained oral feeding. No serious adverse effects or deaths were recorded.

Conclusion Both groups showed improvement in motor function and stabilization of respiratory and bulbar function, with the difference between the groups possibly being related to the earlier treatment initiation. Thus, the present study provides valuable insights into the real-world safety and clinical efficacy of disease-modifying therapies for SMA 1 patients.

Resumo

Antecedentes A atrofia muscular espinhal (AME-5q) é uma doença neurodegenerativa caracterizada por atrofia muscular progressiva, hipotonia e fraqueza. Na AME 1 os sintomas iniciam-se no primeiro semestre de vida. Terapias modificadoras de doença foram aprovadas e demonstram melhores resultados quanto mais cedo forem iniciadas.

Objetivo Descrever a segurança e a eficácia clínica das terapias modificadoras de doença quanto às funções motora, respiratória e bulbar. Os pacientes com AME 1 foram divididos em 2 grupos: os que faziam uso exclusivamente de nusinersena (grupo 1) e os que transacionaram para onasemnogene abeparvovec (OA) (grupo 2).

Métodos Durante 18 meses, os pacientes foram avaliados utilizando a escala Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), marcos do desenvolvimento, necessidade e duração da ventilação, necessidade de suporte nutricional, consistência dos alimentos e sinais de disfagia. Dividiram-se dez pacientes entre os grupos; no grupo 1, a idade média para início do nusinersena foi de 53,6 (12–115) meses e, no grupo 2, a idade foi de 7 (1–12) meses para o nusinersena e 15,2 (10–19) meses para OA.

Resultado Nossos resultados indicam que 70% dos pacientes atingiram algum marco motor, com o grupo 1 aumentando 10,2 pontos na escala CHOP-INTEND, e o grupo 2 aumentando 33. Ademais, 90% dos pacientes não apresentaram declínio respiratório e 30% mantiveram alimentação oral. Não houve efeitos adversos graves ou mortes.

Conclusão Ambos os grupos apresentaram melhoria na função motora e estabilização da função respiratória e bulbar, com a diferença entre os grupos sendo possivelmente relacionada com o início mais precoce do tratamento. Assim, este estudo fornece informações valiosas sobre a segurança e eficácia clínica destas terapias para pacientes com AME 1.

Keywords

Survival of Motor Neuron 1 Protein - Muscular Atrophy, Spinal - Genetic Therapy

Palavras-chave

Proteína 1 de Sobrevivência do Neurônio Motor - Atrofia Muscular Espinhal - Terapia Genética

Authors' Contributions

BKAMFA: data collection, formal analysis, writing – original draft, and writing – review & and editing; APQCA, FNS, MGR: conceptualization, methodology, critical review, and writing – review & editing. All authors discussed the results and contributed to the final manuscript.

Editor-in-Chief: Hélio A. G. Teive.

Associate Editor: Edmar Zanoteli.

Publikationsverlauf

Eingereicht: 10. April 2024

Angenommen: 02. August 2024

Artikel online veröffentlicht:
06. November 2024

• References

• 1 Darras BT. Spinal muscular atrophies. Pediatr Clin North Am 2015; 62 (03) 743-766
• 2 Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol 2011; 68 (08) 979-984
• 3 Crawford TO, Paushkin SV, Kobayashi DT. et al; Pilot Study of Biomarkers for Spinal Muscular Atrophy Trial Group. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One 2012; 7 (04) e33572
• 4 Prior TW, Krainer AR, Hua Y. et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009; 85 (03) 408-413
• 5 Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N. Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next. Annu Rev Genomics Hum Genet 2020; 21: 231-261
• 6 Rodrigues NR, Owen N, Talbot K, Ignatius J, Dubowitz V, Davies KE. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum Mol Genet 1995; 4 (04) 631-634
• 7 Simard LR, Rochette C, Semionov A, Morgan K, Vanasse M. SMN(T) and NAIP mutations in Canadian families with spinal muscular atrophy (SMA): genotype/phenotype correlations with disease severity. Am J Med Genet 1997; 72 (01) 51-58 . Doi: 10.1002/(sici)1096-8628(19971003)72:1<51::aid-ajmg11>3.0.co;2-t
• 8 Velasco E, Valero C, Valero A, Moreno F, Hernández-Chico C. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD541 and SMA phenotype. Hum Mol Genet 1996; 5 (02) 257-263
• 9 Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15 (03) 228-237 . Doi: 10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9
• 10 Wirth B, Schmidt T, Hahnen E. et al. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling. Am J Hum Genet 1997; 61 (05) 1102-1111 . Doi: 10.1086%2F301608
• 11 Calucho M, Bernal S, Alías L. et al. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord 2018; 28 (03) 208-215
• 12 Chen TH. New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?. Int J Mol Sci 2020; 21 (09) 3297
• 13 Ministério da Saúde. Atrofia Muscular Espinhal (AME) 5q tipos I e II [Internet]. Brasília - DF; 2022 nov. (Protocolos Clínicos e Diretrizes Terapêuticas). Report No.: 784. Disponível em: https://www.gov.br/conitec/pt-br/midias/relatorios/2023/atrofia-muscular-espinhal-ame-5q-tipos-i-e-ii
• 14 Ministério da Saúde. Onasemnogeno abeparvoveque para o tratamento de atrofia muscular espinhal (AME) [Internet]. Brasília - DF; 2022 dez. (Medicamento). Report No.: 793. Disponível em: https://www.gov.br/conitec/pt-br/midias/relatorios/portaria/2022/20221207_relatorio_zolgensma_ame_tipo_i_793_2022.pdf
• 15 Aragon-Gawinska K, Seferian AM, Daron A. et al. Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study. Neurology 2018; 91 (14) e1312-e1318
• 16 Finkel RS, Mercuri E, Darras BT. et al; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med 2017; 377 (18) 1723-1732
• 17 Lowes LP, Alfano LN, Arnold WD. et al. Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy. Pediatr Neurol 2019; 98: 39-45
• 18 Mendell JR, Al-Zaidy S, Shell R. et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med 2017; 377 (18) 1713-1722
• 19 Mendell JR, Al-Zaidy SA, Lehman KJ. et al. Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy. JAMA Neurol 2021; 78 (07) 834-841
• 20 Pane M, Coratti G, Sansone VA. et al; Italian Expanded Access Program Working Group. Nusinersen in type 1 spinal muscular atrophy: Twelve-month real-world data. Ann Neurol 2019; 86 (03) 443-451
• 21 Finkel RS, Mercuri E, Meyer OH. et al; SMA Care group. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord 2018; 28 (03) 197-207
• 22 Mercuri E, Finkel RS, Muntoni F. et al; SMA Care Group. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord 2018; 28 (02) 103-115
• 23 Zanoteli E, Araujo APQC, Becker MM. et al. Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy. Arq Neuropsiquiatr 2024; 82 (01) 1-18
• 24 Alves RMR, Calado APM, Van Der Linden V, Bello MAFC, Andrade LB. Brazilian version of the CHOP INTEND scale: cross-cultural adaptation and validation. Arq Neuropsiquiatr 2023; 81 (09) 816-824
• 25 Cances C, Vlodavets D, Comi GP. et al; ANCHOVY Working Group. Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study. Orphanet J Rare Dis 2022; 17 (01) 300
• 26 Finkel RS, McDermott MP, Kaufmann P. et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014; 83 (09) 810-817
• 27 Kolb SJ, Coffey CS, Yankey JW. et al; NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol 2017; 82 (06) 883-891
• 28 Mercuri E, Lucibello S, Perulli M. et al. Longitudinal natural history of type I spinal muscular atrophy: a critical review. Orphanet J Rare Dis 2020; 15 (01) 84
• 29 Acsadi G, Crawford TO, Müller-Felber W. et al. Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study. Muscle Nerve 2021; 63 (05) 668-677
• 30 Govoni A, Gagliardi D, Comi GP, Corti S. Time Is Motor Neuron: Therapeutic Window and Its Correlation with Pathogenetic Mechanisms in Spinal Muscular Atrophy. Mol Neurobiol 2018; 55 (08) 6307-6318
• 31 Belančić A, Strbad T, Kučan Štiglić M, Vitezić D. Effectiveness of Nusinersen in Type 1, 2 and 3 Spinal Muscular Atrophy: Croatian Real-World Data. J Clin Med 2023; 12 (08) 2839
• 32 Erdos J, Wild C. Mid- and long-term (at least 12 months) follow-up of patients with spinal muscular atrophy (SMA) treated with nusinersen, onasemnogene abeparvovec, risdiplam or combination therapies: A systematic review of real-world study data. Eur J Paediatr Neurol 2022; 39: 1-10
• 33 Pechmann A, Behrens M, Dörnbrack K. et al; SMArtCARE study group. Effect of nusinersen on motor, respiratory and bulbar function in early-onset spinal muscular atrophy. Brain 2023; 146 (02) 668-677
• 34 Al-Zaidy SA, Kolb SJ, Lowes L. et al. AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort. J Neuromuscul Dis 2019; 6 (03) 307-317
• 35 Stettner GM, Hasselmann O, Tscherter A, Galiart E, Jacquier D, Klein A. Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study. BMC Neurol 2023; 23 (01) 88
• 36 Mendonca R, Ortega A, Matsui C, van der Linden V, Kerstenetzky M, Grossklauss L. et al. Real world safety and exploratory efficacy of gene therapy for patients with 5q-Spinal Muscular Atrophy in a Brazilian cohort. 2023
• 37 de Holanda Mendonça R, Jorge Polido G, Ciro M, Jorge Fontoura Solla D, Conti Reed U, Zanoteli E. Clinical Outcomes in Patients with Spinal Muscular Atrophy Type 1 Treated with Nusinersen. J Neuromuscul Dis 2021; 8 (02) 217-224
• 38 Pechmann A, Langer T, Schorling D. et al. Evaluation of Children with SMA Type 1 Under Treatment with Nusinersen within the Expanded Access Program in Germany. J Neuromuscul Dis 2018; 5 (02) 135-143