Neural Cell News Volume 13.12 | Apr 3 2019

TOP STORY

Specification of Positional Identity in Forebrain Organoids

Scientists presented a system to trigger a Sonic Hedgehog (SHH) protein gradient in developing forebrain organoids that enabled ordered self-organization along dorso-ventral and antero-posterior positional axes. Consistent with its behavior in vivo, SHH exhibited long-range signaling activity in organoids. [Nat Biotechnol] Abstract

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Senolytic Therapy Alleviates Aβ-Associated Oligodendrocyte Progenitor Cell Senescence and Cognitive Deficits in an Alzheimer’s Disease Model

Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in oligodendrocyte progenitor cell (OPC) function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. [Nat Neurosci] Abstract

LRRK2 Modifies α-Syn Pathology and Spread in Mouse Models and Human Neurons

Investigators performed a targeted genetic screen of risk genes associated with Parkinson’s disease (PD) and parkinsonism for modifiers of alpha-synuclein (α-syn) aggregation, using an α-syn preformed-fibril induction assay. They found that decreased expression of Lrrk2 and Gba modulated α-syn aggregation in mouse primary neurons. Conversely, α-syn aggregation increased in primary neurons from mice expressing the PD-linked LRRK2 G2019S mutation. [Acta Neuropathol] Full Article

NRG1 Type I Dependent Autoparacrine Stimulation of Schwann Cells in Onion Bulbs of Peripheral Neuropathies

Transgenic overexpression of neuregulin-1 (NRG1) type I in Schwann cells on a wildtype background was sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which caused onion bulb formations and resulted in a peripheral neuropathy reminiscent of Charcot-Marie-Tooth Disease 1A . [Nat Commun] Full Article

Reactivation of Nonsense-Mediated mRNA Decay Protects against C9orf72 Dipeptide-Repeat Neurotoxicity

The authors validated that C9orf72 hexanucleotide repeat expansion products could lead to the accumulation of nonsense-mediated mRNA decay (NMD) substrates and identified arginine-rich dipeptide repeats, including poly glycine-arginine and poly proline-arginine, as the main culprits of NMD inhibition. In human SH-SY5Y neuroblastoma cells and in mouse brains, expression of glycine-arginine with 36 repeats was sufficient to cause NMD inhibition. [Brain] Abstract

Loss of Postnatal Quiescence of Neural Stem Cells through mTOR Activation upon Genetic Removal of Cysteine String Protein-α

In cell culture, stem cells in hippocampal neurospheres displayed alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway was the primary cause of neurogenesis deregulation in the absence of cysteine string protein-α (CSP-α). In addition, radial glia-like cells lost quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. [Proc Natl Acad Sci USA] Abstract

Target Identification Reveals Lanosterol Synthase as a Vulnerability in Glioma

Researchers showed that MI-2 exerted its antitumor activity in glioma largely independent of its ability to target menin. They demonstrated that MI-2 activity in glioma was mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. [Proc Natl Acad Sci USA] Abstract

Prophylactic TLR9 Stimulation Reduces Brain Metastasis through Microglia Activation

Investigators showed that systemic prophylactic administration of a toll-like receptor (TLR) 9 agonist, CpG-C, was effective against brain metastases. Acute and chronic systemic administration of CpG-C reduced tumor cell seeding and growth in the brain in three tumor models in mice, including metastasis of human and mouse lung cancer, and spontaneous melanoma-derived brain metastasis. [PLoS Biol] Full Article

Activating a Reserve Neural Stem Cell Population In Vitro Enables Engraftment and Multipotency after Transplantation

Scientists demonstrated that horizontal basal cells (HBCs) in culture arose from both tissue-derived HBCs and multipotent globose cells. Treatment with retinoic acid induced neuronal and non-neuronal differentiation and primed cultured HBCs for transplantation into the lesioned olfactory epithelium (OE). Engrafted HBCs generated all OE cell types, including olfactory sensory neurons, confirming that HBC multipotency and neurocompetency were maintained in culture. [Stem Cell Reports] Full Article

Stearoyl CoA Desaturase Is Essential for Regulation of Endoplasmic Reticulum Homeostasis and Tumor Growth in Glioblastoma Cancer Stem Cells

Researchers reported that glioblastoma stem-like cells depended on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase, which promoted ER homeostasis, cytoprotection, and tumor initiation. [Stem Cell Reports] Full Article | Graphical Abstract

Nuciferine Inhibits the Progression of Glioblastoma by Suppressing the SOX2-AKT/STAT3-Slug Signaling Pathway

Nuciferine (NF) inhibited the proliferation, mobility, stemness, angiogenesis, and epithelial-to-mesenchymal transition of glioblastoma cells. Additionally, NF induced apoptosis and G2 cell cycle arrest. Slug expression was also decreased by NF via the AKT and STAT3 signaling pathways. [J Exp Clin Cancer Res] Full Article

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The Role of SVZ Stem Cells in Glioblastoma

The authors summarize current findings about links between neural stem cells and cancer stem cells in glioblastoma and discuss current therapeutic approaches, which arise as a result of identifying the cell of origin in glioblastoma. [Cancers] Abstract | Download Full Article

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Two BrainStorm Scientific Abstracts Accepted for Presentation

BrainStorm Cell Therapeutics Inc. announced that two scientific abstracts have been accepted for presentation. [Press release from BrainStorm Cell Therapeutics Inc. discussing research to be presented at the 71^st American Academy of Neurology (AAN) Annual Meeting, Philadelphia] Press Release

Inaugural AACR-Novocure Tumor Treating Fields Research Grant Recipients Announced

The recipients of the American Association for Cancer Research (AACR)-Novocure Tumor Treating Fields research grants were announced. The grants represent a joint effort between Novocure and the AACR to promote and support innovative research on Tumor Treating Fields. [Press release from Novocure discussing research presented at American Association for Cancer Research (AACR) Annual Meeting 2019, Atlanta] Press Release

Tesetaxel Brain Concentrations Exceeded Concentrations Required for Tumor Killing for Sustained Period of Time in Preclinical Testing

Odonate Therapeutics, Inc. presented results of preclinical studies of tesetaxel, Odonate’s investigational, orally administered taxane. [Press release from Odonate Therapeutics, Inc. discussing research presented at the American Association for Cancer Research (AACR) Annual Meeting 2019, Atlanta] Press Release

vTv Therapeutics to Present at the 14^th International Conference on Alzheimer’s & Parkinson’s Diseases

The presentation will describe the post-hoc analyses of MRI brain volume measures, brain FDG-PET measures of glucose uptake and plasma markers of inflammation in a subgroup of patients with type 2 diabetes, defined as having glycosylated hemoglobin greater than 6.5%, and mild Alzheimer’s disease in the azeliragon Phase III study, STEADFAST. [Press release from vTv Therapeutics Inc. discussing research presented at the 14^th International Conference on Alzheimer’s & Parkinson’s Diseases, Lisbon] Press Release

Data in Parkinson’s Disease Model in Non-Human Primates Demonstrate Reversal of Cognitive Deficits with Novel NMDA Receptor Modulator, NYX-458

Aptinyx Inc. announced positive preclinical data on its novel NMDA receptor modulator, NYX-458, demonstrating reversal of cognitive deficits in a non-human primate model of Parkinson’s disease. [Press release from Aptinyx Inc. discussing data presented at the 14^th International Conference on Alzheimer’s & Parkinson’s Diseases, Lisbon] Press Release

Humanigen Announces Preliminary Results from Ifabotuzumab Phase I Study Accepted for Presentation

Humanigen, Inc. announced that preliminary results from an ongoing phase I bioimaging study of the company’s proprietary anti-EphA3 monoclonal antibody, ifabotuzumab, in patients with recurrent GBM have been accepted for presentation, [Press release from Humanigen, Inc. discussing research presented at American Association for Cancer Research (AACR) Annual Meeting 2019, Atlanta] Press Release

United Neuroscience to Present Data on Alzheimer’s Vaccine

United Neuroscience announced an upcoming presentation on Phase IIa results of its lead clinical product, UB-311. [Press release from United Neuroscience (PR Newswire Association LLC.) discussing data presented at the 14^th International Conference on Alzheimer’s & Parkinson’s Diseases, Lisbon] Press Release

Stridebio and Takeda Sign Collaboration and License Agreement to Advance Novel Gene Therapies for Neurological Diseases

StrideBio, Inc. announced the signing of a collaboration and license agreement with Takeda Pharmaceutical Company Limited to develop in vivo adeno associated viral based therapies for Friedreich’s Ataxia and two additional undisclosed targets. [StrideBio, Inc.] Press Release

Data Safety Monitoring Board Recommends Continuation of Phase III Clinical Studies of Bace Inhibitor Elenbecestat in Early Alzheimer’s Disease

Eisai Co., Ltd. announced that in the 8^th meeting of the Data Safety Monitoring Board (DSMB) for the global Phase III clinical studies on the investigational oral beta amyloid cleaving enzyme inhibitor elenbecestat in early Alzheimer’s disease, the DSMB reviewed safety data including the potential for decline in cognition, and recommended the continuation of the studies. [Eisai Co., Ltd.] Press Release

DelMar Pharmaceuticals Receives Approval from MD Anderson Cancer Center’s IRB for Protocol Expansion to Include Maintenance Stage MGMT-Unmethylated GBM Patients in Ongoing Phase II Trial of VAL-083

DelMar Pharmaceuticals, Inc. announced the University of Texas MD Anderson Cancer Center’s Institutional Review Board has approved a trial protocol amendment to expand DelMar’s ongoing Phase II clinical trial of VAL-083 in patients with MGMT-unmethylated glioblastoma. [DelMar Pharmaceuticals, Inc.] Press Release

Amylyx Pharmaceuticals Announces First Patients Dosed in PEGASUS Phase II Trial of AMX0035 in Alzheimer’s Disease and Expansion of the Trial

Amylyx Pharmaceuticals, Inc., in collaboration with the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation and the Cure Alzheimer’s Fund, announced the dosing of its first patients in a recently expanded Phase II clinical trial (PEGASUS) to assess AMX0035 in individuals with Alzheimer’s disease. [Amylyx Pharmaceuticals, Inc. (Business Wire, Inc.)] Press Release

MediciNova Announces Results of Subgroup Analysis from the SPRINT-MS Phase IIb Trial of MN-166 in Progressive MS

MediciNova, Inc. announced results from its subgroup analysis of the SPRINT-MS Phase IIb trial of MN-166 in progressive multiple sclerosis. [MediciNova, Inc.] Press Release

resTORbio Announces Initiation of Phase Ib/IIa Trial of RTB101 in Parkinson’s Disease

resTORbio, Inc. announced the initiation of a Phase Ib/IIa trial of RTB101, its orally administered, small molecule, potent inhibitor of target of rapamycin complex 1 (TORC1) product candidate, alone or in combination with sirolimus, in Parkinson’s disease. [resTORbio, Inc.] Press Release

Inovio Completes Enrollment Ahead of Schedule in Immuno-Oncology Study for Glioblastoma (GBM) with INO-5401 in Combination with Regeneron’s PD-1 Inhibitor

Inovio Pharmaceuticals, Inc. announced that its Phase I/II immuno-oncology trial in patients with newly diagnosed glioblastoma has completed its enrollment three months ahead of schedule. [Inovio Pharmaceuticals, Inc.] Press Release

Alector Initiates Phase I Trial of AL003 for the Treatment of Patients with Alzheimer’s Disease

Alector, Inc. announced the initiation of the first-in-human Phase I trial for AL003, called the INTERCEPT study. [Alector, Inc.] Press Release

Imvax Announces Positive Results from Clinical Trial of Novel Igv-001 Autologous Cell Vaccine in Treating Patients with Newly Diagnosed Glioblastoma

Imvax, Inc. announced positive results from an ongoing Phase Ib clinical trial that demonstrate treatment with IGV-001, the company’s novel autologous tumor cell vaccine, outperformed standard of care with prolonged overall survival and progression-free survival in patients with newly diagnosed glioblastoma multiforme. [Imvax, Inc.] Press Release

Selumetinib Granted US Breakthrough Therapy Designation in Neurofibromatosis Type 1

AstraZeneca and MSD, Inc. announced that the FDA has granted Breakthrough Therapy Designation for the MEK 1/2 inhibitor and potential new medicine selumetinib. [AstraZeneca] Press Release

Incysus Therapeutics Announces FDA Approval of Ind Application for a Novel Gamma-Delta (γδ) T Cell Therapy for Treatment of Patients with Newly-Diagnosed Glioblastoma

Incysus Therapeutics, Inc. announced that the FDA has approved the Investigational New Drug application for the clinical study of a genetically modified γδ T cell in combination with chemotherapy for the treatment of patients with newly-diagnosed glioblastoma. [Incysus Therapeutics, Inc. (GlobeNewswire, Inc.)] Press Release

FDA Approves Mavenclad^® (Cladribine) Tablets as First and Only Short-Course Oral Treatment for Relapsing-Remitting and Active Secondary Progressive Multiple Sclerosis

EMD Serono announced that the FDA has approved MAVENCLAD^® tablets for the treatment of adults with relapsing-remitting disease and active secondary progressive disease. [EMD Serono (PR Newswire Association LLC.)] Press Release

Ziopharm Oncology Announces FDA Fast Track Designation for Ad-Rts-hIL-12 Plus Veledimex for the Treatment of Recurrent Glioblastoma

Ziopharm Oncology, Inc. announced that the FDA has granted Fast Track Designation for its Controlled IL-12 program, or Ad-RTS-hIL-12 plus veledimex, for the treatment of recurrent or progressive glioblastoma multiforme in adults. [Ziopharm Oncology, Inc.] Press Release

BioArctic Receives Grant from Vinnova for a Collaborative Research Project to Increase Brain Uptake of Antibodies

BioArctic AB announced that the company has received a non-diluting grant of MSEK 5 from Sweden’s Innovation Agency, Vinnova, for a collaborative research project between industry and academia to develop multi-specific antibodies intended for immunotherapy in central nervous system diseases. [BioArctic AB] Press Release

India’s Clinical-Trial Rules to Speed Up Drug Approvals

India has announced new rules for clinical trials that will speed up drug approvals and remove the requirement for large studies to test the efficacy of drugs that have already been approved in other nations. The country will also introduce regulations for universities undertaking research involving people. [Nature News] Editorial

Staff Scientists at the University of California Set to Form a First-of-Its-Kind Union

There are 5,000 of them within the University of California system, with titles like project scientist or professional researcher. They’re not on the tenure track, but they power one of the world’s most prolific research institutions. Now, organizers are in the final stages of setting up a first-of-its-kind union exclusively for academic researchers who are not faculty, postdocs, or graduate students. [STAT News] Editorial

NEW Gordon Research Conference: Excitary Synapses & Brain Function
June 9-14, 2019
Manchester, New Hampshire, United States

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NEW Postdoctoral Position – Retinal Stem Cell Biology (Johns Hopkins University)

NEW Postdoctoral Position – Developmental Neurobiology (University of Liège)

Senior Scientist – Neuroscience (STEMCELL Technologies Inc.)

Postdoctoral Fellow – Alcohol & Adult Neurogenesis (The University of Texas at Austin)

Staff Scientist – Development of Mechanism-Based Tumor Therapies (Frankfurt Cancer Institute)

Postdoctoral Research Fellow – Neuroscience (The University of Texas at Austin)

Postdoctoral Researcher – Neurobiology (University of Rochester)

Staff Scientist – Molecular & Behavioral Neuroscience (Fred Hutchinson Cancer Research Center)

Postdoctoral Research Associate – Neurological Diseases (University of Utah)

Research Associate – iPSC & Neurodegenerative Disease (TU Dresden)

Postdoctoral Position – Neurophysiology (University Medical Center Hamburg Eppendorf)

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