Intrathecal injection of scAAV9-hIGF1 prolongs the survival of ALS model mice by inhibiting the NF-kB pathway

Publication date: Available online 12 February 2018 Source:Neuroscience Author(s): HaoJie Hu, HuiQian Lin, WeiSong Duan, Can Cui, ZhongYao Li, YaKun Liu, Wan Wang, Di Wen, Ying Wang, ChunYan Li Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motor neurons. Currently, there is no effective drug for ALS. Recent studies in ALS model mice have shown that insulin-like growth factor-1 (IGF1) may be a promising therapeutic drug. We demonstrate that self-complementary adeno-associated virus serum type 9 encoding the human IGF1 (scAAV9-hIGF1) could significantly postpone the onset and slow down the progression of the disease owning to inhibiting the NF-κB signalling pathway. Furthermore, the results were supported by experiments in which the CRISPR/Cas9 system was used to knock-down IGF1 in ALS mice (mIGF1). Our data indicate that IGF1-mediated suppression of NF-κB activation in microglia is novel molecular mechanism underlying MN death in ALS. It provides new insight of IGF1 and points towards novel therapeutic target of IGF1 in ALS. Graphical abstract
Source: Neuroscience - Category: Neuroscience Source Type: research

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Purpose of review Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS. Recent findings The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental...
Source: Current Opinion in Neurology - Category: Neurology Tags: MOTOR NEURON DISEASE: Edited by Jeremy Shefner and Shafeeq S. Ladha Source Type: research
by Michael D. Ehlers, MD, PhD Dr. Ehlers is with Biogen in Cambridge, Massachusetts. Innov Clin Neurosci. 2018;15(3–4):15–16 Funding: No funding was received for the preparation of this article. Disclosures: Dr. Ehlers is an employee and shareholder at Biogen Inc. in Cambridge, Massachusetts. Prominent and expensive failures in Alzheimer’s disease therapies have led to a contagious belief system in some parts of the biopharma industry that neuroscience is just too hard, too risky, and too uncertain. But, might this belief system itself be a residual bias of the past? Close inspection reveals all the signs...
Source: Innovations in Clinical Neuroscience - Category: Neuroscience Authors: Tags: Commentary Current Issue Source Type: research
In conclusion, we report a convenient and noninvasive ALS treatment method. Our results revealed a previously unrecognized role of IGF1 in p38 MAPK and the JNK-mediated pathway and its potential role as a therapeutic target for ALS. PMID: 29499331 [PubMed - as supplied by publisher]
Source: Brain Research Bulletin - Category: Neurology Authors: Tags: Brain Res Bull Source Type: research
Publication date: Available online 12 February 2018 Source:Neuroscience Author(s): HaoJie Hu, HuiQian Lin, WeiSong Duan, Can Cui, ZhongYao Li, YaKun Liu, Wan Wang, Di Wen, Ying Wang, ChunYan Li Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motor neurons. Currently, there is no effective drug for ALS. Recent studies in ALS model mice have shown that insulin-like growth factor-1 (IGF1) may be a promising therapeutic drug. We demonstrate that self-complementary adeno-associated virus serum type 9 encoding the human IGF1 (scAAV9&ndas...
Source: Neuroscience - Category: Neuroscience Source Type: research
In conclusion, the present study demonstrated that TIGIT is a prominent negative immune regulator involved in immunosenescence. This novel finding is highly significant, as targeting TIGIT might be an effective strategy to improve the immune response and decrease age-related comorbidities. Delivery of Extracellular Vesicles as a Potential Basis for Therapies https://www.fightaging.org/archives/2018/01/delivery-of-extracellular-vesicles-as-a-potential-basis-for-therapies/ Here I'll point out a readable open access review paper on the potential use of extracellular vesicles as a basis for therapy: harveste...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Publication date: 4 December 2017 Source:Neuroscience, Volume 365 Author(s): Dongxiao Li, Chong Liu, Chunxing Yang, Dan Wang, Dongxia Wu, Yinkuang Qi, Qin Su, Guangping Gao, Zuoshang Xu, Yansu Guo Mutant SOD1 causes amyotrophic lateral sclerosis (ALS) by a dominant gain of toxicity. Previous studies have demonstrated therapeutic potential of mutant SOD1-RNAi delivered by intrathecal (IT) injection of recombinant adeno-associated virus (rAAV). However, optimization of delivery is needed to overcome the high degree of variation in the transduction efficiency and therapeutic efficacy. Here, on the basis of our previously def...
Source: Neuroscience - Category: Neuroscience Source Type: research
Our research is devoted to the identification of efficient strategies to target the central nervous system (CNS) and to the development of novel therapies for motor neuron disorders. In particular, using the unique therapeutic potential of self-complementary adeno-associated virus (AAV) vectors, we recently elaborated a new gene therapy strategy for a genetic form of Amyotrophic Lateral Sclerosis (ALS), a lethal disease with limited therapeutic options. Approximately 20% of familial ALS cases are caused by mutations in the Superoxide Dismutase 1 (SOD1) gene and toxic gain of function of the mutant protein.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Publication date: Available online 24 August 2017 Source:Neuroscience Research Author(s): Kuniyuki Endo, Shinsuke Ishigaki, Yoshito Masamizu, Yusuke Fujioka, Akiya Watakabe, Tetsuo Yamamori, Nobuhiko Hatanaka, Atsushi Nambu, Haruo Okado, Masahisa Katsuno, Hirohisa Watanabe, Masanori Matsuzaki, Gen Sobue Fused in sarcoma (FUS) is an RNA binding protein that is involved in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To establish the common marmoset (Callithrix jacchus) as a model for FTLD, we generated a stereotaxic injection-based marmoset model of FUS-silencing. We designed shRNAs aga...
Source: Neuroscience Research - Category: Neuroscience Source Type: research
ABSTRACT Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, although it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here, we describe two novel lines of mice that overexpress either 10 pure or 102 interrupted GGGGCC repeats mediated by adeno-associated virus (AAV) ...
Source: DMM Disease Models and Mechanisms - Category: Biomedical Science Authors: Tags: Neurodegenerative disorders RESEARCH ARTICLE Source Type: research
by Tomohiro Ishii, Emiko Kawakami, Kentaro Endo, Hidemi Misawa, Kazuhiko Watabe TAR DNA-binding protein 43 (TDP-43) is a main constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We have previously demonstrated that adenovirus-transduced artificial TDP-43 cytoplasmic aggregates forma tion is enhanced by proteasome inhibitionin vitro andin vivo. However, the relationship between cytoplasmic aggregate formation and cell death remains unclear. In the present study, rat neural stem cell lines stably transfected with EGFP- or Sirius-e...
Source: PLoS One - Category: Biomedical Science Authors: Source Type: research
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