SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?

Swoboda, Kathryn J.

doi:10.1172/jci74142

Cited by 3 publications

(2 citation statements)

References 22 publications

(14 reference statements)

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“…33 A return of function to pre-existing 'dysfunctional' axons possibly at the cusp of degeneration is another postulated process by which chronically denervated motor units respond to SMN2 enhancing therapies. 34 Our findings may support emerging biological concepts of reversible pathophysiology in affected neurones including restoration of neuromuscular junction function, 35 improved synaptic and neuronal cell trafficking, 36 and/ or reversal of axonal conduction block, 37 with commencement of therapy.…”

Section: Discussionsupporting

confidence: 63%

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

Kariyawasam

D’Silva

Howells

et al. 2020

J Neurol Neurosurg Psychiatry

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ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function.InterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

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Section: Discussionsupporting

confidence: 63%

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

Kariyawasam

D’Silva

Howells

et al. 2020

J Neurol Neurosurg Psychiatry

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“…Humans and bonobos are the only species in which two copies of paralogous inverted SMN genes in chromosome 5 are present [18]. The paralogous gene SMN2 differs from SMN1 by a single C-to-T transition in exon 7 that modifies a splicing modulator and causes deletion of exon 7 in 90% of SMN2 mRNA transcripts [19].…”

Section: Introductionmentioning

confidence: 99%

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Simone

Ramirez

Bucchia

et al. 2015

Cell. Mol. Life Sci.

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Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development.

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Spinal muscular atrophy—recent therapeutic advances for an old challenge

et al. 2015

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In the past decade, improved understanding of spinal muscular atrophy (SMA) aetiopathogenesis has brought us to a historical turning point: we are at the verge of development of disease-modifying treatments for this hitherto incurable disease. The increasingly precise delineation of molecular targets within the survival of motor neuron (SMN) gene locus has led to the development of promising therapeutic strategies. These novel avenues in treatment for SMA include gene therapy, molecular therapy with antisense oligonucleotides, and small molecules that aim to increase expression of SMN protein. Stem cell studies of SMA have provided an in vitro model for SMA, and stem cell transplantation could be used as a complementary strategy with a potential to treat the symptomatic phases of the disease. Here, we provide an overview of established data and novel insights into SMA pathogenesis, including discussion of the crucial function of the SMN protein. Preclinical evidence and recent advances from ongoing clinical trials are thoroughly reviewed. The final remarks are dedicated to future clinical perspectives in this rapidly evolving field, with a broad discussion on the comparison between the outlined therapeutic approaches and the remaining open questions.

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SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?

Cited by 3 publications

References 22 publications

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Spinal muscular atrophy—recent therapeutic advances for an old challenge

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