Combinatorial treatment for spinal muscular atrophy

Spinal muscular atrophy (SMA) is a motoneuron disease caused by the loss of the geneSMN1, encoding a protein essential for motoneuron survival. Additional copies of an alternateSMN gene,SMN2, are present in the genome, but exon 7 is skipped in SMN2 mRNA producing an unstable protein (SMN Δ7). Therapeutic approaches for SMA include (1) viral‐mediated replacement ofSMN1, (2) antisense oligonucleotide (ASO) or small molecule mediated correction SMN2 splicing, and (3) increasedSMN2 expression induced by histone deacetylase (HDAC) inhibitors. This Editorial highlights this study by Pagliarni et al. in which they used combined treatment of cell models of SMA with an ASO and an orally delivered HDAC inhibitor (panobinostat) to overcome the limitations of a single ‐therapeutic approach. AbstractSpinal muscular atrophy (SMA) is a severe autosomal recessive motor neuron disease caused by the loss ofSMN1, which encodes a protein essential for motor neuron survival. SMA patients have one or more copies of an alternateSMN gene,SMN2, which is nearly identical toSMN1.SMN2 differs at a single nucleotide fromSMN1 which results in the skipping of exon 7 in the mRNA and produces an unstable protein (SMN Δ7). Therapeutic approaches that have been undertaken include (1) replacement ofSMN1 by gene delivery mediated by adeno ‐associated virus serotype 9 (AAV9) (Zolgensma), (2) correction of the aberrantSMN2 splicing using an antisense oligonucleotide (ASO) or small molecule (nusin...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: EDITORIAL HIGHLIGHT Source Type: research

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Abstract Objective: To review the efficacy and safety of onasemnogene abeparvovec-xioi (Zolgensma) in the treatment of spinal muscular atrophy (SMA). Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to December 2019) was completed using the terms onasemnogene, AVXS-101, and spinal muscular atrophy. Manufacturer prescribing information, article bibliographies, and data from were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on were incorporated in the reviewed data. Data Synthesis: Onasemnogene i...
Source: The Annals of Pharmacotherapy - Category: Drugs & Pharmacology Authors: Tags: Ann Pharmacother Source Type: research
Publication date: Available online 21 February 2020Source: The Journal of Molecular DiagnosticsAuthor(s): Bo Liu, Yulan Lu, Bingbing Wu, Lin Yang, Renchao Liu, Huijun Wang, Xinran Dong, Gang Li, Qian Qin, Wenhao Zhou
Source: The Journal of Molecular Diagnostics - Category: Pathology Source Type: research
The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or poss...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Tags: Cell Mol Life Sci Source Type: research
Spinal muscular atrophy (SMA) is a rare, autosomal recessive inherited disease caused by a homozygote deletion of exon 7 in the SMN1 (survival motor neuron) gene. SMA is characterized by degeneration of anterior horn cells of the spinal cord and brainstem resulting in muscular atrophy and proximal muscle weakness [1, 2]. The disease is classified into five subtypes according to age of presentation and severity of symptoms. There is no clear delineation between subtypes in many cases, and SMA is regarded as a spectrum [3].
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Spinal muscular atrophy (SMA) is a leading genetic cause of infant death, influenced by the copy number of two highly homologous genes: SMN1 and SMN2. Although exome sequencing is widely applied for genetic testing, SMA diagnosis and carrier screening have not been incorporated in routine exome sequencing data analysis and lack evaluation in clinical applications. We established a workflow for the SMN gene copy number analysis based on uniquely mapped reads on exon 7 of SMN genes and the control region.
Source: Journal of Molecular Diagnostics - Category: Pathology Authors: Tags: Regular article Source Type: research
Spinal muscular atrophy (SMA) is among the most common monogenic causes of spinal motor neuron(SMN) degeneration with severely affected cases having a median survival of less than 2 years of age. Nusinersen (Spinraza) is a novel antisense oligonucleotide administered intrathecally for treatment of SMA. Most of these patients have scoliosis often treated by posterior fusion from T2 to sacrum making lumbar puncture challenging. Building on our prior experience in intrathecal catheter placement, we describe our initial experience with an image-guided approach to implantation of intrathecal catheters and subcutaneous ports in ...
Source: Journal of Vascular and Interventional Radiology : JVIR - Category: Radiology Authors: Tags: Scientific Session 38 Source Type: research
The progressive and sometimes deadly congenital neuromuscular disorder, spinal muscular atrophy (SMA), is the result of degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem secondary to a dysfunction of survival motor neuron (SMN) protein. One of the current treatment options involves scheduled intrathecal injections of an antisense oligonucleotide that splices into the typically dysfunctional SMN2 gene, Spinraza (Biogen, USA). Prospective trials analyzing the outcomes of Spinraza injections in SMA patients, including the multicenter ENDEAR trial, have showed survival benefit in infants.
Source: Journal of Vascular and Interventional Radiology : JVIR - Category: Radiology Authors: Tags: Scientific Traditional Poster Source Type: research
r R Abstract 5‑q-associated spinal muscular atrophy (SMA) has so far been a causally untreatable disease, which leads to severe, progressive physical restrictions due to the loss of spinal motor neurons. However, the monogenetic cause of the relatively short coding "survival motor neuron" (SMN) 1 gene sequence and the presence of almost identical gene copies, the SMN2 genes, offer favorable conditions for the development of new therapeutic approaches. While previously only supportive and palliative therapies could be used, new disease-modifying drugs are now available for the first time. Nusinerse...
Source: Der Nervenarzt - Category: Neurology Authors: Tags: Nervenarzt Source Type: research
AbstractIn amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially expressSynaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients,SYT13 is enriched in both OMNs and the remaini...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
This study emphasizes the lack of understanding of the architecture of the SMN region as well as the cause of SMA in the black SA population. These factors need to be taken into account when counseling and performing diagnostic testing in black populations.
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
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