Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients

Wurster, Claudia D.; Winter, Benedikt; Wollinsky, K. H.; Ludolph, Albert C.; Uzelac, Zeljko; Witzel, Simon; Schocke, Michael; Schneider, Ralf; Kocak, Tugrul

doi:10.1007/s00415-018-9124-0

Cited by 93 publications

(97 citation statements)

References 48 publications

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“…A comparison of radiation dosages between studies was limited because of the different units (mSv versus mGy * cm) and different statistical values (median versus mean) used. 4,5,16 A recent monocentric study described a mean exposure of 89 mGy * cm (range 9-892 mGy * cm). 4 Another group reported median DLP that was higher in patients with spinal fusion (246.5 mGy * cm) than in patients without prior spinal operation (90.4 mGy * cm).…”

Section: Discussionmentioning

confidence: 99%

Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy

Cordts

Lingor

Friedrich

et al. 2020

Ther Adv Neurol Disord

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Background: Intrathecal administration of nusinersen in adult spinal muscular atrophy (SMA) patients presents challenges owing to severe scoliosis and previous spinal surgery with metal implantation. In patients with a complex spinal situation, the potential risks of the intrathecal administration may lead to delayed treatment initiation. Methods: In this study, we analyzed 53 CT-guided lumbar punctures of 11 adult nonambulatory SMA type 2 and 3 patients. All patients had scoliosis and six patients had previously undergone metal implantation. Results: Drug administration was successful in 100% of the patients and none of the patients opted for treatment discontinuation. Complete osseous fusion precluded conventional posterior interlaminar access in eight lumbar punctures in four patients, which required alternative routes including transforaminal punctures and translaminar drilling. Median duration of all lumbar punctures was 9 min and median radiation exposure was 100 mGy* cm. The most common adverse event was post-lumbar puncture syndrome that occurred in five lumbar punctures (9.4%). Conclusions: Our data demonstrate that nusinersen can be successfully, safely, and rapidly administered in adult SMA patients with complex spinal conditions and suggest the translaminar drilling technique as an alternative delivery route. Therefore, intrathecal nusinersen treatment should not be withheld from patients because of severe spine deformities, however, drug efficacy in adult SMA patients needs to be investigated in further studies.

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Section: Discussionmentioning

confidence: 99%

Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy

Cordts

Lingor

Friedrich

et al. 2020

Ther Adv Neurol Disord

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“…This splice modification of the SMN2 pre‐mRNA increases the amount of full‐length SMN protein and thus compensates for the genetic defect in the SMN1 gene (Bennett, Baker, Pham, Swayze, & Geary, ; Wurster & Ludolph, ). Because of its inability to cross the blood–brain barrier, nusinersen requires intrathecal administration (Stolte, Totzeck, & Kizina, ; Wurster, Winter, et al, ). This treatment has shown encouraging results in children with infantile‐onset (SMA 1) and later‐onset (SMA 2) SMA (Darras, Chiriboga, et al, ; Finkel et al, ; Mercuri, Darras, & Chiriboga, ; Michelson et al, ; Pane et al, ), but efficacy data for adult patients are pending, while current treatment costs are high (Editorial, The Lancet Neurology, ).…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

Keßler

Latzer

Schmid

et al. 2020

Journal of Neurochemistry

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abbreviations: ABC, ammonium bicarbonate; ACN, acetonitrile; ALSFRS-R, amyotrophic lateral sclerosis functional rating scale-revised; APC, absolute protein cluster; ASO, antisense oligonucleotide; CDH18, cadherin 18; COL6A1, collagen type VI alpha 1; CPE, carboxypeptidase E; CSF, cerebrospinal fluid; DDA, data-dependent acquisition; DPC, differential protein cluster; DTT, dithiothreitol; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; HFMSE, hammersmith functional rating scale expanded; IAA, iodoacetamide; IgG, immunoglobulin G; IPA, ingenuity pathway analysis; IQR, interquartile range; LFQ, label-free quantification; MS, mass spectrometry; N/A, not applicable; NPTX1, neuronal pentraxin-1; OCB, oligoclonal immunoglobulin G (IgG) bands; PARK7, Parkinson's disease protein 7; PCA, principle component analysis; pNfH, plasma phosphorylated neurofilament heavy chain; Q alb , CSF/ serum quotients of albumin; rpm, rounds per minute; RRID, Research Resource Identifier (see scicrunch.org); SEM, standard error of the mean; SEMA7A, semaphorin 7A; SMA, 5q-linked spinal muscular atrophy; SMN1, survival motor neuron 1 gene; SMN2, survival motor neuron 2 gene; T 0 , first nusinersen injection at baseline; T 10 , sixth nusinersen injection after 10 months; TFA, trifluoracetic acid; WPCNA, weighted protein correlation network analysis; ΔHFMSE (T 0 -T 10 ), change in Hammersmith Functional Rating Scale Expanded score between T 0 and T 10 . AbstractPromising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes in the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age-and gender-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via P...

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“…These trials include a phase I safety study of IT of scAAV9/JeT-GAN for the treatment of giant axonal neuropathy (GAN) (NCT02362438), and three studies evaluating the safety and efficacy of nusinersen (ISIS 396443) administered by IT route to participants with infantile-onset Spinal Muscular Atrophy (SMA), later onset SMA, and presymptomatic SMA (NCT02193074/ NCT02292537 and NCT02462759). In December 2016, the Food and Drug Administration approved the antisense oligonucleotide Spiranza (nusinersen) for treatment of SMA [104].…”

Section: Potential Gene Therapy Approaches For Late Onset Pompe Diseamentioning

confidence: 99%

Advancements in AAV-mediated Gene Therapy for Pompe Disease

Salabarria

Nair

Clément

et al. 2020

JND

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Pompe disease (glycogen storage disease type II) is caused by mutations in acid ␣-glucosidase (GAA) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient's immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy.

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Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients

Cited by 93 publications

References 48 publications

Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy

Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

Advancements in AAV-mediated Gene Therapy for Pompe Disease

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