Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study

Finkel, Richard S.; Chiriboga, Claudia A.; Vajsar, Jiri; Day, John W.; Montes, Jacqueline; Vivo, Darryl C. De; Yamashita, Mason; Rigo, Frank; Hung, Gene; Schneider, Eugene; Norris, Daniel A.; Xia, Shuting; Bennett, C. Frank; Bishop, Kathie M.

doi:10.1016/s0140-6736(16)31408-8

Cited by 873 publications

(807 citation statements)

References 30 publications

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“…Accordingly, many SMA patients had nonmucocutaneous candidiasis, which usually only occurs in immunodeficient individuals 25. Moreover, pulmonary infection, especially pneumonia, appears to be a common feature of SMA patients 26, 27, 28, 29, 30. Decreased respiratory efficiency and stasis of secretions can increase risk of infections 29, 31.…”

Section: Potential Functional Consequences Of Lymphoid Organ Defectsmentioning

confidence: 99%

“…With the most recent FDA approval of nusinersen (Spinraza), which represents the first approved drug for the treatment of SMA, it will be instrumental to continue to understand disease etiology. Indeed, while the results of the nusinersen clinical trial looked promising, the treated patients still lag far behind healthy individuals on motor functions 30. Thus, it is critical to understand and target various pathways involved in SMA pathogenesis that may not currently be covered with by Spinraza (restricted to the CNS), such as the peripheral immune organs.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

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New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

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Section: Potential Functional Consequences Of Lymphoid Organ Defectsmentioning

confidence: 99%

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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“…Nusinersen (Spinraza, Biogen, Cambridge, MA, USA) has shown promising results in preclinical, early phase human, and clinical trials (47,57,58). The route of administration is intrathecal due to its poor transport across the blood-brain barrier.…”

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

Recent therapeutic developments of spinal muscular atrophy

Bora¹,

Yeşbek-Kaymaz²,

Bekircan-Kurt³

et al. 2018

Turk J Med Sci

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“…These types of AOs can be used to restore gene function, correct aberrant splicing, produce a novel transcript or even down regulate gene expression [205]. Most notably are Exondys 51 and Nusinersen, which are treatments for Duchenne muscular dystrophy and spinal muscular atrophy, respectively [207,208]. Exondys 51 gained FDA accelerated approval in September 2016, and is designed to skip DMD exon 51 during pre-mRNA processing in order to restore the open reading frame.…”

Section: Suppression/modification Of Mutant Gene Expression and Protementioning

confidence: 99%

“…Exondys 51 will treat a subset of Duchenne muscular dystrophy patients who have deletions flanking exon 51 [208,209]. Nusinersen gained full FDA approval in December 2016 and provides the only approved treatment for patients with spinal muscular atrophy [207].…”

Section: Suppression/modification Of Mutant Gene Expression and Protementioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study

Cited by 873 publications

References 30 publications

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Recent therapeutic developments of spinal muscular atrophy

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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