Nusinersen potentially effective in SMA

Adams, Louise

doi:10.1038/nrneurol.2016.199

Cited by 7 publications

(9 citation statements)

References 1 publication

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“…Thus, our and other studies suggest that the pharmacological inhibition of JNK pathway could represent an effective potential adjuvant to other-already in use-SMN-dependent therapies for treating SMA disease (like the antisense oligonucleotides nusinersen, Biogen) [129] which constitute a very promising strategy for SMA, but still have some limitations [130].…”

Section: Jnk Role In Spinal Muscular Atrophymentioning

confidence: 77%

JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death

Schellino

Boido

Vercelli

2019

Cells

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The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3. In the developing spinal cord, JNK proteins control neuronal polarity, axon growth/pathfinding, and programmed cell death; in adulthood they can drive degeneration and regeneration, after pathological insults. Indeed, recent studies have highlighted a role for JNK in motor neuron (MN) diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophy. In this review we discuss how JNK-dependent signaling regulates apparently contradictory functions in the spinal cord, in both the developmental and adult stages. In addition, we examine the evidence that the specific targeting of JNK signaling pathway may represent a promising therapeutic strategy for the treatment of MN diseases.

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Section: Jnk Role In Spinal Muscular Atrophymentioning

confidence: 77%

JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death

Schellino

Boido

Vercelli

2019

Cells

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“…Finally, our treatment could represent an effective potential adjuvant to other therapies, like Nusinersen (ISIS 396443), an antisense oligonucleotide (ASO) already used in phase 3 clinical studies to increase the production of full-length SMN2 protein (Adams, 2017 ; Maharshi and Hasan, 2017 ), or AVXS-101, an AAV-based treatment to restore SMN protein expression (Mendell et al, 2017 ). Indeed, the use of ASOs or gene therapy represents a very promising strategy for SMA, as demonstrated by the improvement of motor functions and extended survival observed in mouse models and human patients (Parente and Corti, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Schellino

Boido

Borsello

et al. 2018

Front. Mol. Neurosci.

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Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder that occurs in early childhood. The disease is caused by the deletion/mutation of the survival motor neuron 1 (SMN1) gene resulting in progressive skeletal muscle atrophy and paralysis, due to the degeneration of spinal motor neurons (MNs). Currently, the cellular and molecular mechanisms underlying MN death are only partly known, although recently it has been shown that the c-Jun NH2-terminal kinase (JNK)-signaling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMNΔ7+/+; Smn−/−), we tested a specific JNK-inhibitor peptide (D-JNKI1) on these mice, by chronic administration from postnatal day 1 to 10, and histologically analyzed the spinal cord and quadriceps muscle at age P12. We observed that D-JNKI1 administration delayed MN death and decreased inflammation in spinal cord. Moreover, the inhibition of JNK pathway improved the trophism of SMA muscular fibers and the size of the neuromuscular junctions (NMJs), leading to an ameliorated innervation of the muscles that resulted in improved motor performances and hind-limb muscular tone. Finally, D-JNKI1 treatment slightly, but significantly increased lifespan in SMA mice. Thus, our results identify JNK as a promising target to reduce MN cell death and progressive skeletal muscle atrophy, providing insight into the role of JNK-pathway for developing alternative pharmacological strategies for the treatment of SMA.

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“…To this extent, the tight regulation of autophagy could be a good strategy to increase the therapeutic potential as a complementary therapy against SMA, possibly in combination with the emerging promising treatments aimed at manipulating the SMN expression (e.g. nusinersen) 61 , 62 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy

et al. 2017

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Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, due to homozygous mutations or deletions in the telomeric survival motoneuron gene 1 (SMN1). SMA is characterized by motor impairment, muscle atrophy, and premature death following motor neuron (MN) degeneration. Emerging evidence suggests that dysregulation of autophagy contributes to MN degeneration. We here investigated the role of autophagy in the SMNdelta7 mouse model of SMA II (intermediate form of the disease) which leads to motor impairment by postnatal day 5 (P5) and to death by P13. We first showed by immunoblots that Beclin 1 and LC3-II expression levels increased in the lumbar spinal cord of the SMA pups. Electron microscopy and immunofluorescence studies confirmed that autophagic markers were enhanced in the ventral horn of SMA pups. To clarify the role of autophagy, we administered intracerebroventricularly (at P3) either an autophagy inhibitor (3-methyladenine, 3-MA), or an autophagy inducer (rapamycin) in SMA pups. Motor behavior was assessed daily with different tests: tail suspension, righting reflex, and hindlimb suspension tests. 3-MA significantly improved motor performance, extended the lifespan, and delayed MN death in lumbar spinal cord (10372.36 ± 2716 MNs) compared to control-group (5148.38 ± 94 MNs). Inhibition of autophagy by 3-MA suppressed autophagosome formation, reduced the apoptotic activation (cleaved caspase-3 and Bcl2) and the appearance of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons, underlining that apoptosis and autophagy pathways are intricately intertwined. Therefore, autophagy is likely involved in MN death in SMA II, suggesting that it might represent a promising target for delaying the progression of SMA in humans as well.

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Nusinersen potentially effective in SMA

Cited by 7 publications

References 1 publication

JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death

JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy

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