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Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing

ABSTRACT: Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing

PROVIDER: PRJNA854081 | ENA |

REPOSITORIES: ENA

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Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing

Project description:Defect in the SMN1 gene causes spinal muscular atrophy (SMA), which shows loss of motor nerve cells, muscle weakness and atrophy. While current treatment strategies including small molecules or viral vectors improved motor function and survival, an ultimate treatment is highly challenging to correct the endogenous mutations by genome-editing technologies. We have developed the CRISPR-Cas9 based homology-independent targeted integration (HITI) strategy, which allowed for DNA knock-in in both dividing and non-dividing cells in vivo. Here, we demonstrated a gene correction of mutant mSmn1 by using the HITI strategy to treat SMA model mice. To provide the long-term therapeutic benefits of gene correction, we established a unique approach to treat SMA by combination with gene cDNA supplementation and editing (Gene-DUET). As a proof of concept of therapeutic approach for SMA, we demonstrated the advantageous effects including motor function and survival improvement by Gene-DUET strategy in SMA model mice. The Gene-DUET represents a powerful strategy for treating inherited diseases especially for neurodegenerative disorders as well as neuromuscular diseases.

2024-06-17 | GSE207181 | GEO

Transcription profiling of muscular and neuronal mouse mutant: spinal muscular atrophy(SMA)

Project description:Study of gene expression profiles of muscular and neuronal mouse mutant of spinal muscular atrophy(SMA). Pre and post symptomatic stage disease have been analyzed.

2005-05-20 | E-MEXP-131 | biostudies-arrayexpress

Increased Systemic HSP70B Levels in Spinal Muscular Atrophy Infants

Project description:RNA sequencing in whole blood from spinal muscular atrophy patients and healthy control infants

2021-05-08 | GSE174056 | GEO

Transcription profiling of mouse spinal chord from a mouse model of severe spinal muscular atrophy

Project description:Pre-symptomatic development of lower motor neuron connectivity in a mouse model of severe spinal muscular atrophy

2009-12-07 | E-MEXP-2428 | biostudies-arrayexpress

Cell-mediated cytotoxicity surrounding the brain in spinal muscular atrophy

Project description:We here longitudinally investigated how spinal muscular atrophy (SMA) and nusinersen shaped local immune responses in the cerebrospinal fluid (CSF).

2024-04-20 | PXD051600 | Pride

Transcription profiling by array of denervated muscular atrophy

Project description:To elaborate the process of denervated muscular atrophy, and provide scientific basis for the prevention and treatment of denervated muscular atrophy. we performed a time course transcriptomic analysis of denervated muscular atrophy

2019-06-16 | E-MTAB-8009 | biostudies-arrayexpress

Bioenergetics status determines motor neuron vulnerability in spinal muscular atrophy

Project description:Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice to determine the factors underlying their selective vulnerability in sinal muscular atrophy.

2017-04-10 | GSE86908 | GEO

Skeletal muscle mitochondrial dysfunction in spinal muscular atrophy

Project description:Skeletal muscle mitochondrial dysfunction in spinal muscular atrophy

| PRJNA857643 | ENA

Increased Systemic HSP70B Levels in Spinal Muscular Atrophy Infants

Project description:Increased Systemic HSP70B Levels in Spinal Muscular Atrophy Infants

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SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Project description:<p>Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA. </p>

2023-11-27 | MTBLS8784 | MetaboLights

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