P.91Optimization of AAV-mediated gene therapy for SOD1-linked ALS

Amyotrophic Lateral Sclerosis (ALS) is an incurable motor neuron (MN) disorder, characterized by degeneration of MNs leading to progressive paralysis and death within two to five years after diagnosis. Gene therapy is emerging as promising treatment option for patients affected by familial forms of ALS (fALS), representing 10% of all ALS cases. Taking advantage of viral vectors derived from Adeno-Associated Virus serotype 10 (AAV10) and the small nuclear RNA U7, we developed a gene therapy for SOD1-linked ALS (20% of fALS).
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research

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This article provides an evidence-based personal perspective on the future of cell and gene therapy for degenerative diseases of the intervertebral disc. This paper focuses on how mammalian protein production platforms and transfected and irradiated protein packaging cell lines may be used as “cellular factories” for overproduction of therapeutic proteins and proanabolic growth factors, particularly in the context of regenerative therapies. This paper also speculates on future opportunities and challenges in this area of research and how new innovations in biotechnology affect cell a nd gene therapy for degenerative diseases.
Source: Neurosurgery Clinics of North America - Category: Neurosurgery Authors: Source Type: research
AbstractAmyotrophic Lateral Sclerosis (ALS), a debilitating neurodegenerative disorder is related to mutations in a number of genes, and certain genes of the Ribonuclease (RNASE) superfamily trigger ALS more frequently. Even though missense mutations in Angiogenin (ANG) and Ribonuclease 4 (RNASE4) have been previously shown to cause ALS through loss-of-function mechanisms, understanding the role of rare variants with a plausible explanation of their functional loss mechanisms is an important mission. The study aims to understand if any of the rare ANG and RNASE4 variants catalogued in Project MinE consortium caused ALS due...
Source: Metabolic Brain Disease - Category: Neurology Source Type: research
Publication date: Available online 15 November 2019Source: Stem Cell ResearchAuthor(s): Xia Gao, Xin Gao, Haiyan Zhao, Weijing Cui, Mei Tan, Hui DengAbstractPeripheral blood mononuclear cells (PBMCs) were collected from a 6-year-old female child who was clinically diagnosed as primary nephrotic syndrome (NS) with hormone resistance. An iPSC line was successfully established by the Sendai-virus (SeV) delivery system. The iPS-19 (GSPHi001-A) expressed pluripotent markers, exhibited a normal karyotype and differentiated towards three germ layers. The iPSC line might offer a potentially useful tool for investigating mechanisms...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
ConclusionsOur studies unveil new insights into water-associated structural changes of SOD1 nonnative trimers and demonstrate that in situ incorporation of (2,6-aza)Trp is a sensitive and powerful tool for probing subtle changes of water environments during protein aggregation.General significanceThe water-sensitive probe, (2,6-aza)Trp, demonstrates superior sensitivity for detecting modulation of water microsolvation, structural conformation during oligomer formation and 5FUrd binding to both wild type and mutant SOD1.Graphical abstract
Source: Biochimica et Biophysica Acta (BBA) General Subjects - Category: Biochemistry Source Type: research
Mir-17∼92 Confers Motor Neuron Subtype Differential Resistance to ALS-Associated Degeneration. Cell Stem Cell. 2019 May 21;: Authors: Tung YT, Peng KC, Chen YC, Yen YP, Chang M, Thams S, Chen JA Abstract Progressive degeneration of motor neurons (MNs) is the hallmark of amyotrophic lateral sclerosis (ALS). Limb-innervating lateral motor column MNs (LMC-MNs) seem to be particularly vulnerable and are among the first MNs affected in ALS. Here, we report association of this differential susceptibility with reduced expression of the mir-17∼92 cluster in LMC-MNs prior to disease onset. Reduced mir-...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research
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
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
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
Conclusions:Identification of the mechanisms of neuronal differential vulnerability may lead to development of new therapeutic strategies that prevent the progressive neurodegeneration in MN diseases.Study Supported by: Cariplo Foundation to SC (2012-0513), Thierry Latran Foundation to SC and EH, JPND; 529-2014-7500 to SC and EH; ARISLA to SC.Disclosure: Dr. Nizzardo has nothing to disclose. Dr. Rizzo has nothing to disclose. Dr. Taiana has nothing to disclose. Dr. Allodi has nothing to disclose. Dr. Aguila Benitez has nothing to disclose. Dr. Nijssen has nothing to disclose. Dr. Ulzi has nothing to disclose. Dr. Melzi has...
Source: Neurology - Category: Neurology Authors: Tags: Neuromuscular and Clinical Neurophysiology (EMG): Motor Neuron Disease I Source Type: research
Abstract Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific a...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
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