Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Masson, Riccardo; Mazurkiewicz‐Bełdzińska, Maria; Rose, Kristy; Servais, Laurent; Xiong, Hui; Zanoteli, Edmar; Baranello, Giovanni; Bruno, Claudio; Day, John W.; Deconinck, Nicolas; Klein, Andrea; Mercuri, Eugenio; Vlodavets, D.; Wang, Yi; Dodman, Angela; El-Khairi, Muna; Gorni, Ksenija; Jaber, Birgit; Kletzl, Heidemarie; Gaki, Eleni; Fontoura, Paulo; Darras, Basil T.; Volpe, Joseph J.; Posner, John; Kellner, Ulrich; Quinlivan, Rosaline C. M.; Gerber, Marianne; Khwaja, Omar; Scalco, R.; Seabrook, Timothy J.; Koch, Armin; Balikova, Irina; Joniau, Inge; Accou, Geraldine; Tahon, Valentine; Wittevrongel, S.; Vos, Elke De; Mendonça, Rodrigo de Holanda; Matsui, Ciro; Darcie, Ana Letícia Fornazieri; Machado, Cleide; Oyamada, Maria Kiyoko; Martini, Joyce; Polido, Graziela Jorge; Iannicelli, Juliana Rodrigues; Ferreira, Juliana Caires de Oliveira Achili; Hu, Chaoping; Zhu, Xiaomei; Chen, Qian; Шен, Ли; Li, Hui; Shi, Yiyun; Zhou, Shuizhen; Xiao, Ying; Zhou, Zhenxuan; Wang, Sujuan; Sang, Tian; Cui, Wei; Dong, Hui; Cao, Yiwen; Wen, Jing; Li, Wenzhu; Qin, Lun Xiu; Barišić, Nina; Celovec, Ivan; Delic, Martina Galiot; Ivkić, Petra Kristina; Vukojević, Nenad; Kern, Ivana; Najdanovic, B; Skugor, Marin; Tomas, Josipa; Boespflug‐Tanguy, Odile; Lucia, Silvana De; Seferian, Andrea; Barreau, Emmanuel; Mnafek, Nabila; Peche, Helene; Grange, Allison; Nguyen, Diem Trang; Milaščević, Darko; Tachibana, Shunsuke; Pagliano, Emanuela; Marzoli, Stefania Bianchi; Santarsiero, Diletta; Sierra, Myriam Garcia; Tremolada, Gemma; Arnoldi, Maria Teresa; Viganó, M. E. F; Dosi, Claudia; Zanin, Riccardo; Schembri, Veronica; Brolatti, Noemi; Rao, Giuseppe; Tassara, Elisa; Morando, Simone; Tacchetti, Paola; Pedemonte, Marina; Priolo, Enrico; Sposetti, Lorenza; Comi, Giacomo Pietro; Govoni, Alessandra; Osnaghi, Silvia; Minorini, Valeria; Abbati, Francesca; Fassini, Federica; Foà, Michaela; Lopopolo, Amalia; Pane, Marika; Palermo, Concetta; Pera, Maria Carmela; Amorelli, Giulia Maria; Barresi, Costanza; D’Amico, Guglielmo; Orazi, Lorenzo; Coratti, Giorgia; Leone, Daniela; Antonaci, Laura; Sanctis, Roberto De; Berti, Beatrice; Kimura, N.; Takeshima, Yasuhiro; Shimomura, Hideki; Lee, Tomoko; Gomi, Fumi; Morimatsu, Takanobu; Furukawa, Toru; Stodolska-Koberda, Urszula; Waskowska, Agnieszka; Kolendo, Jagoda; Sobierajska-Rek, Agnieszka; Modrzejewska, Sandra; Lemska, Anna; Melnik, Evgenia; Artemieva, Svetlana; Leppenen, Natalya; Yupatova, Nataliya; Monakhova, Anastasya; Papina, Yulia; Shidlovsckaia, Olga; Литвинова, Елена; Enzmann, Cornelia; Galiart, Elea; Gugleta, Konstantin; Haschke, Christine Wondrusch; Topaloǧlu, Haluk; Öncel, İbrahim; Ertugrul, Nesibe Eroglu; Konuşkan, Bahadır; Eldem, Bora; Kadayıfçılar, Sibel; Alemdaroğlu, I.; Sari, Seher; Bilgin, Neslihan; Karaduman, Aynur Ayşe; Sarikaya, Fatma Gökçem Yildiz; Graham, Robert J.; Ghosh, Partha S.; Casavant, David; Levine, Alexis; Titus, Rachael; Engelbrekt, Amanda; Ambrosio, Lucia; Fulton, Anne B.; Baglieri, Anna Maria; Dias, Courtney; Maczek, Elizabeth; Pasternak, Amy; Beres, Shannon; Duong, Tina; Gee, Richard; Young, Sally Dunaway

doi:10.1016/s1474-4422(22)00339-8

Cited by 50 publications

(24 citation statements)

References 28 publications

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“…After 24 months of treatment, 18 infants (44%) were able to sit without support for at least 30 seconds. However, no infants could stand alone after 24 months of treatment [154].…”

Section: Clinical Trials Clinical Trials Involving Symptomatic Patientsmentioning

confidence: 98%

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

Nishio

Niba

Saitô

et al. 2023

IJMS

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Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.

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“…After 24 months of treatment, 18 infants (44%) were able to sit without support for at least 30 seconds. However, no infants could stand alone after 24 months of treatment [154].…”

Section: Clinical Trials Clinical Trials Involving Symptomatic Patientsmentioning

confidence: 98%

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

Nishio

Niba

Saitô

et al. 2023

IJMS

Self Cite

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show abstract

“…These treatments include an antisense oligonucleotide, nusinersen; a small molecule splicing modifier, risdiplam; and gene therapy with onasemnogene abeparvovec-xioi. [33][34][35] These treatments are quickly becoming routine components of care for early-onset SMA. The advent of these new therapies has led to the consideration of new SMA phenotypes and redefinition of the natural history of this condition.…”

Section: Spinal Muscular Atrophymentioning

confidence: 99%

“…However, in recent years treatments with novel mechanisms of action have been developed that increase the expression of the survival motor neuron protein. These treatments include an antisense oligonucleotide, nusinersen; a small molecule splicing modifier, risdiplam; and gene therapy with onasemnogene abeparvovec-xioi 33-35 . These treatments are quickly becoming routine components of care for early-onset SMA.…”

Section: Motor Neuron Disordersmentioning

confidence: 99%

Genetic Myelopathies

Stavros

2024

CONTINUUM: Lifelong Learning in Neurology

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OBJECTIVE This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy. LATEST DEVELOPMENTS Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia. ESSENTIAL POINTS Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.

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“…It is likely that some of these diseases have prenatal onset and so fetal therapy strategies may need to be considered in the future. Nevertheless, as is the case for many early onset genetic disorders (Pearson et al, 2021;Fumagalli et al, 2022;Masson et al, 2022;Strauss et al, 2022), such therapies have the potential to significantly modify disease at different stages of the disease course, which can significantly improve patient lifespan and quality of life.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

Roth

Kilpinen²,

Kurian³

et al. 2023

Front. Cell Dev. Biol.

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Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models.

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Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Cited by 50 publications

References 28 publications

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

Genetic Myelopathies

Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

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