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Combinatorial treatment for spinal muscular atrophy: An Editorial for 'Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cell

脊髓性肌萎缩的组合治疗: 组蛋白去乙酰化酶抑制剂 LBH589 和剪接开关反义寡核苷酸联合治疗增强脊髓性肌萎缩细胞中 SMN2 剪接和 SMN 表达的社论

  • 影响因子:4.26
  • DOI:10.1111/jnc.14974
  • 作者列表:"Poletti A","Fischbeck KH
  • 发表时间:2020-02-14
Abstract

:Spinal muscular atrophy (SMA) is a severe autosomal recessive motor neuron disease caused by the loss of SMN1, which encodes a protein essential for motor neuron survival. SMA patients have one or more copies of an alternate SMN gene, SMN2, which is nearly identical to SMN1. SMN2 differs at a single nucleotide from SMN1 which results in the skipping of exon 7 in the mRNA and produces an unstable protein (SMNΔ7). Therapeutic approaches that have been undertaken include (1) replacement of SMN1 by gene delivery mediated by adeno-associated virus serotype 9 (AAV9) (Zolgensma), (2) correction of the aberrant SMN2 splicing using an antisense oligonucleotide (ASO) or small molecule (nusinersin, risdiplam), and (3) increased expression of SMN2 mediated by histone deacetylase (HDAC) inhibitors. Two of these three approaches have given rise to successful treatments for SMA, but they are very expensive, and their long-term safety is not well known. In addition, the ability of ASOs and viral vectors to reach their targets in the CNS with peripheral administration is limited. Small molecules may cross the brain-blood barrier when orally delivered and can be discontinued if needed to mitigate adverse effects. 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. Panobinostat enhanced the expression of SMN2, increasing the amount of SMN2 mRNA available for splicing correction mediated by the ASO. In addition, panobinostat increased exon 7 retention in the SMN2 mRNA. This combinatorial treatment might allow lower or less frequent ASO doses, reducing the need for repeated intrathecal administration. The combined effects of panobinostat and nusinersen can now be tested in SMA animal models to determine whether this approach will be translatable to patients.

摘要

: 脊髓性肌萎缩症 (SMA) 是由 SMN1 丢失引起的一种严重的常染色体隐性遗传运动神经元疾病,SMN1 编码一种运动神经元存活所必需的蛋白。SMA 患者有一个或多个备用 SMN 基因 SMN2 的拷贝,与 smn1 几乎相同。SMN2 与 SMN1 在单个核苷酸上存在差异,这导致 mRNA 中外显子 7 的跳跃,并产生不稳定的蛋白 (smn Δ 7)。已经进行的治疗方法包括 (1) 通过腺相关病毒血清型 9 (AAV9) (Zolgensma) 介导的基因递送替代 SMN1,(2) 使用反义寡核苷酸 (ASO) 或小分子 (nusinersin,risdiplam) 和 (3) 校正异常 SMN2 剪接组蛋白去乙酰化酶 (HDAC) 抑制剂介导的 SMN2 表达增加。这三种方法中的两种已经成功地治疗了 SMA,但是它们非常昂贵,并且它们的长期安全性并不为人所知。此外,ASOs 和病毒载体在外周给药的 CNS 中达到靶标的能力有限。口服给药时,小分子可能会穿过脑-血屏障,如果需要,可以停药以减轻不良反应。这篇社论强调了 Pagliarni 等人的这项研究,他们使用 ASO 和口服 HDAC 抑制剂 (panobinostat) 联合治疗 SMA 细胞模型克服单一治疗方法的局限性。Panobinostat 增强了 SMN2 的表达,增加了 ASO 介导的可用于剪接校正的 SMN2 mRNA 的量。此外,panobinostat 增加了 SMN2 mRNA 中外显子 7 的保留。这种组合治疗可能允许较低或较不频繁的 ASO 剂量,减少重复鞘内给药的需要。现在可以在 SMA 动物模型中测试 panobinostat 和 nusinersen 的联合作用,以确定这种方法是否可以翻译给患者。

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发表时间:2020-01-01
DOI:10.1111/bpa.12761
作者列表:["Sebastián-Serrano Á","Simón-García A","Belmonte-Alfaro A","Pose-Utrilla J","Santos-Galindo M","Del Puerto A","García-Guerra L","Hernández IH","Schiavo G","Campanero MR","Lucas JJ","Iglesias T"]

METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

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影响因子:3.66
发表时间:2020-01-24
DOI:10.3233/JAD-191069
作者列表:["Mendes FR","Leclerc JL","Liu L","Kamat PK","Naziripour A","Hernandez D","Li C","Ahmad AS","Doré S"]

METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.

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