Human Growth Hormone Increases SMN Expression and Survival in Severe Spinal Muscular Atrophy Mouse Model

MacKenzie, Duncan S.; Shamim, Fahad; Mongeon, Kevin; Trivedi, Ankur; MacKenzie, Alex; Farooq, Faraz

doi:10.3233/jnd-140000

Cited by 5 publications

(4 citation statements)

References 45 publications

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“…Finally, Stat5a also displays a decreased expression in BAT from RL SMA mice and is upregulated in CL. Increased activation of Stat5 has previously been demonstrated to induce SMN expression ( 84 ) and pharmacological compounds that increase Stat5 improve disease phenotypes in SMA cellular and animal models ( 85 , 86 ). Thus, the beneficial influence of light modulation on SMA pathology may be due to the cumulative effect of not one, but several molecular changes.…”

Section: Discussionmentioning

confidence: 99%

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter

Koch

Betts

et al. 2018

Human Molecular Genetics

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Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn−/−;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.

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Section: Discussionmentioning

confidence: 99%

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter

Koch

Betts

et al. 2018

Human Molecular Genetics

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“…2,58,59 The STAT5 pathway has been implicated in the activation of SMN2 promoter. [60][61][62] The human lactation hormone prolactin (PRL) and human growth hormone (HGH) have been shown to activate the STAT5 pathway which results in an increase in both SMN2 gene transcription and full-length SMN protein both in vitro and in vivo, resulting in attenuation of the SMA mouse model severity. PRL treatment resulted in significant survival and attenuation of disease phenotype in the SMA mouse model, a possible reflection of the significant SMN induction observed with PRL treatment in vivo.…”

Section: Smn2-dependent Therapiesmentioning

confidence: 99%

Current and emerging treatment options for spinal muscular atrophy

Farooq¹,

MacKenzie²

2015

DNND

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Spinal muscular atrophy is one of the most common inherited neuromuscular conditions; our understanding of the genetic pathology and translational research coming from this insight has made significant progress over the past decade. This short review provides the background of the disease along with the bench to bedside progress of some promising treatment options to develop better understanding of the present state of the disease.

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“…SMA is caused by deletion or mutation of both copies of the survival motor neuron 1 ( SMN1 ) gene, which encodes SMN, a protein necessary for proper motor neuron development and function. The severity of SMA symptoms is dependent on the variable copy number of the related gene SMN2 ; patients with higher levels of SMN2 expression have less severe symptoms . C5-substituted quinazolines were found to be potent inducers of SMN2 expression, but the molecular target was not known. , In subsequent protein microarray array studies using a radio-labeled C5-substituted analogue, this class of compounds was found to bind and inhibit DcpS. , Candidate C5-quinazoline inhibitor RG3039 was advanced as a potential SMA therapy, where it was shown to improve survival and motor function in SMA mice. , RG3039 showed promising results during a phase 1 clinical trial, but its development as a SMA therapy was later terminated due to an inability to increase SMN1 protein levels in humans .…”

Section: Introductionmentioning

confidence: 99%

“…The severity of SMA symptoms is dependent on the variable copy number of the related gene SMN2; patients with higher levels of SMN2 expression have less severe symptoms. 21 C5-substituted quinazolines were found to be potent inducers of SMN2 expression, but the molecular target was not known. 22,23 In subsequent protein microarray array studies using a radiolabeled C5-substituted analogue, this class of compounds was found to bind and inhibit DcpS.…”

Section: ■ Introductionmentioning

confidence: 99%

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

et al. 2022

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The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders.

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Human Growth Hormone Increases SMN Expression and Survival in Severe Spinal Muscular Atrophy Mouse Model

Cited by 5 publications

References 45 publications

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Current and emerging treatment options for spinal muscular atrophy

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

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