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May 2015

Komatsu M, Wheeler HE, Chung S, Low SK, Wing C, Delaney SM, Gorsic LK, Takahashi A, Kubo M, Kroetz DL, Zhang W, Nakamura Y, Dolan ME

Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy

Clin Cancer Res [Epub ahead of print]

Publication Date: May 26, 2015

Product Type: iCell GABANeurons

Summary:

iCell Neurons in combination with clinical GWAS studies for chemotherapy-induced peripheral neuropathies (CIPN) were used to identify the most promising genetic variants and genes associated with CIPN underlying ethnic specificity. iCell Neurons were used to validate gene function through the use of gene knockdown by siRNA transfection and neurite outgrowth assessment.

Impact:

iCell Neurons offer a relevant in vitro cell model to assist with the elucidation of variants specific to the Asian population that may be helpful in developing personalized cancer treatments.

April 2015

Pellett S, Tepp WH, Scherf JM, Pier, CL and Johnson EA

Activity of Botulinum Neurotoxin Type D (Strain 1873) in Human Neurons

Toxicon. 101: 63 - 9

Publication Date: April 30, 2015

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to examine BoNT/D activity, a lesser known BoNT derivative, in human cells. The results showed that BoNT/D can enter and cleave VAMP 2 but at a significantly lower efficiency and shorter duration of action than BoNT/A1, the common serotype used in the cosmetic industry and to a lesser degree as a therapeutic.

Impact:

This study supports the need to explore other serotypes, besides the more well-known types, that could be considered a potential bioterrorism attack and for potential use as a novel therapeutic or drug delivery method. iCell Neurons are a relevant human model to detect BoNT and further characterize its properties.

Chatzidaki A, Fouillet A, Li J, Dage J, Millar NS, Sher E, Ursu D

Pharmacological Characterisation of Nicotinic Acetylcholine Receptors Expressed in Human iPSC-Derived Neurons

PLoS One 10(4):e0125116

Publication Date: April 23, 2015

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to examine the expression and functional properties of nicotinic acetylcholine receptors (nAChRs). Gene expression analysis indicated the presence of transcripts encoding several nAChR subunits, α3-α7, β1, β2, and β4 subunits. In addition, similarly high transcript levels were detected for the truncated dupα7 subunit transcript, encoded by the partially duplicated gene CHRFAM7A, which has been associated with psychiatric disorders such as schizophrenia.

Impact:

Neuronal nAChRs have been implicated in a variety of neurological and psychiatric disorders, including Alzheimer’s disease, schizophrenia, depression and ADHD, thus drawing considerable interest, from both academia and pharma, in developing novel cellular assays. These cells therefore represent a great tool to advance the understanding of the properties of native human nAChRs.

February 2015

Diouf B, Crews KR, Lew G, Pei D, Cheng C, Bao J, Zheng JJ, Yang W, Fan Y, Wheeler HE, Wing C, Delaney SM, Komatsu M, Paugh SW, McCorkle JR, Lu X, Winick NJ, Carroll WL, Loh ML, Hunger SP, Devidas M, Pui CH, Dolan ME, Relling MV, Evans WE

Association of an Inherited Genetic Variant with Vincristine-related Peripheral Neuropathy in Children with Acute Lymphoblastic Leukemia

JAMA 313(8):815-23

Publication Date: February 24, 2015

Product Type: iCell GABANeurons

Summary:

 iCell Neurons were used to assess chemotherapeutic (vincristine)-induced toxicity and the relationship between CEP72 expression and the degree of patient sensitivity to vincristine. These data corroborate their clinical finding that an inherited polymorphism in CEP72 is associated with an increased risk and severity of vincristine-related peripheral neuropathy.

Impact:

iCell Neurons confirmed clinical findings of a genetic link to the risk and severity of chemotherapeutic-induced neuropathy. These findings may provide basis for safer dosing of the widely used anticancer agent vincristine.

October 2014

Scherf JM, Hu XS, Tepp WH, Ichtchenko K, Johnson EA, Pellett S

Analysis of Gene Expression in Induced Pluripotent Stem Cell-Derived Human Neurons Exposed to Botulinum Neurotoxin A Subtype 1 and a Type A Atoxic Derivative

PLoS One 9(10):e111238

Publication Date: October 22, 2014

Product Type: iCell GABANeurons

Summary:

iCell Neurons were exposed to BoNT and an inactive BoNT derivative to analyze the BoNTs effects on gene expression. Significant transcriptional changes were observed at 14 days post intoxication, specifically in genes related to Ca2+ channel signaling and neurite sprouting.

Impact:

An inactive BoNT derivative has been proposed as a general delivery vehicle to target compounds to neurons. iCell Neurons provided a human model to assess the effects of BoNT and variants to investigate this delivery method.

June 2014

Alhebshi AH, Odawara A, Gotoh M, and Suzuki I

Thymoquinone Protects Cultured Hippocampal and Human Induced Pluripotent Stem Cells-derived Neurons against α-synuclein-induced Synapse Damage

Neurosci Lett 570:126-31

Publication Date: June 6, 2014

Product Type: iCell GABANeurons

Summary:

Synapse density, synaptic vesicle recycling and electrical activity were assessed in iCell Neurons before and after treatment with α-synuclein and thymoquinone (TQ). iCell Neurons exhibited toxicity to α-synuclein, which was reduced upon treatment with TQ.

Impact:

Neuroprotection against synapse damage associated with Parkinson’s disease was demonstrated in iCell Neurons, providing evidence that these cells are a relevant system to discover potential therapeutics for neurodegenerative diseases.

January 2014

Dage JL, Colvin EM, Fouillet A, Langron E, Roell WC, Li J, Mathur SX, Mogg AJ, Schmitt MG, Felder CC, Merchant KM, Isaac J, Broad LM, Sher E, and Ursu D

Pharmacological Characterisation of Ligand- and Voltage-gated Ion Channels Expressed in Human iPSC-derived Forebrain Neurons

Psychopharmacology (Berl) 231(6):1105-24

Publication Date: January 7, 2014

Product Type: iCell GABANeurons

Summary:

Gene expression analysis and functional characterization (using FLIPR) of the ion channels (Ca and Na) and receptors (AMPA, NMDA, and GAB) involved in synaptic physiology were performed on iCell Neurons.

Impact:

This study demonstrated that iCell Neurons show higher correlation with the prefrontal cortex and they exhibit functional ionotropic glutamate receptors (AMPA and NMDA) and GABAA receptors. iCell Neurons are a good cellular model of a forebrain human neuron population that can be used both as a control or host of genetic mutations in genetic neurological disease studies (ASD).

Odawara A, Saitoh Y, Alhebshi AH, Gotoh M, and Suzuki I

Long-term Electrophysiological Activity and Pharmacological Response of a Human Induced Pluripotent Stem Cell-derived Neuron and Astrocyte Co-culture

Biochem Biophys Res Commun 443(4):1176-81

Publication Date: January 7, 2014

Product Type: iCell GABANeurons

Summary:

iCell Neurons were co-cultured with rat primary astrocytes to study the effects of a co-culture environment on the longevity, spontaneous firing activity and drug response on the neurons as measured by MEA.

Impact:

iCell Neurons were maintained in culture with the rat astrocytes for an extend period of time (>120 days) and they were able to maintain long-term spontaneous firing that can be modulated with synapse antagonists drugs and detect synchronicity.

August 2013

Whitemarsh RC, Tep WH, Bradshaw M, Lin G, Pier CL, Scherf JM, Johnson EA, and Pellett S

Characterization of Botulinum Neurotoxin A Subtypes 1 through 5 by Investigation of Activities in Mice, in Neuronal Cell Cultures, and In Vitro

Infect Immun 81(10):3894-902

Publication Date: August 5, 2013

Product Type: iCell GABANeurons

Summary:

iCell Neurons, along with other commonly used in vitro and in vivo models, were used to characterize the various subtypes of BoNT/A. The results showed distinct in vitro and in vivo toxicological properties between the mouse bioassay (MBA) and in vitro human cell models, thus questioning the predictivity of the MBA.

Impact:

This study supports the need to consider not only the mode of the testing (in vivo versus in vitro) but also the species of the model when designing potency assays for current and future pharmaceutical BoNT preparations. iCell Neurons area relevant human model to detect BoNT.

June 2013

Grose C, Yu X, Cohrs RJ, Carpenter JE, Bowlin JL, and Gilden D

Aberrant Virion Assembly and Limited Glycoprotein C Production in Varicella-Zoster Virus-infected Neurons

J Virol 87(17):9643-8

Publication Date: June 26, 2013

Product Type: iCell GABANeurons

Summary:

An iCell Neurons in vitro model of varicella zoster virus (VZV) infection developed by Yu, et al. (2013) was used in a subsequent study to determine whether diminished production of virion components and/or final assembly of complete virions play a role in limiting productive virus infection.

Impact:

Primary VZV infection typically produces varicella (chickenpox), after which the virus becomes latent. Reactivation of the virus produces zoster (shingles), which is a more serious disease characterized by chronic pain and other neurological problems. iCell Neurons are used to model VZV infection and better define the molecular underpinnings of the virus-host relationship.

January 2013

Gill JK, Chatzidaki A, Ursu D, Sher E, and Millar NS

Contrasting Properties of α7-Selective Orthosteric and Allosteric Agonists Examined on Native Nicotinic Acetylcholine Receptors

PLoS One 8(1):e55047

Publication Date: January 29, 2013

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to evaluate the potential use of three pharmacologically distinct α7-selective nicotinic ligands (an orthosteric agonist, a positive allosteric modulator, and a nondesensitizing allosteric agonist) for the characterization of native nAChRs.

Impact:

iCell Neurons were shown to be a relevant human model to identify and characterize ligands that are specific for particular receptor subtypes implicated in neurological and psychiatric disorders. The identification of such reagents will accelerate academic research and pharmaceutical drug discovery.

December 2012

Yu X , Seitz S, Pointon T, Bowlin JL, Cohrs RJ, Jonjić S, Haas J, Wellish M, and Gilden D

Varicella Zoster Virus Infection of Highly Pure Terminally Differentiated Human Neurons

J Neurovirol 19(1):75-81

Publication Date: December 12, 2012

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to develop a novel in vitro model of varicella zoster virus (VZV) infection. Infection of iCell Neurons with VZV yields a non-productive infection with detectable expression of immediate-early, early, and late viral genes, but no evidence of apoptosis, which together will enable molecular analysis of VZV-neuron interactions and mechanisms of VZV reactivation.

Impact:

iCell Neurons provided a biologically relevant human cell model to study mechanisms of VZV infection, which was previously not possible using primary neuronal cells due to limitations in cell functionality and purity.

Xu X, Lei Y, Luo J, Wang J, Zhang S, Yang XJ, Sun M, Nuwaysir E, Fan G, Zhao J, Lei L, and Zhong Z

Prevention of ß-amyloid Induced Toxicity in Human iPS Cell-derived Neurons by Inhibition of Cyclin-dependent Kinases and Associated Cell Cycle Events

Stem Cell Res 10(2):213-27

Publication Date: December 7, 2012

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to develop a novel, robust, and sensitive Aß toxicity-mediated model of Alzheimer’s disease, which was subsequently used in a screen of several hundred compounds from a proprietary GlaxoSmithKline compound library. Nineteen hits were identified, and one hit, a Cdk2 inhibitor, was selected for a follow up study using iCell Neurons to confirm the mechanism of action.

Impact:

iCell Neurons were successfully used to model Alzheimer’s disease and employed in a high-throughput small molecule screen for modulators of the disease phenotype. This is the first known example of iPS cell-derived neurons used in an Aß toxicity screen and demonstrates the use of iCell Neurons for disease modeling and drug screening for neurodegenerative disease.

August 2012

Haythornthwaite A, Stoelzle S, Hasler A, Kiss A, Mosbacher J, George M, Brüggemann A, and Fertig N

Characterizing Human Ion Channels in Induced Pluripotent Stem Cell-derived Neurons

J Biomol Screen 17(9):1264-72

Publication Date: August 24, 2012

Product Type: iCell GABANeurons

Summary:

This characterization study demonstrated that iCell Neurons display cellular electrophysiological properties similar to native human neurons using manual and automated patch clamp recordings.

Impact:

iCell Neurons exhibit electrophysiological characteristics similar to native human neurons and thus provide a relevant in vitro model for disease modeling, drug discovery, and toxicity testing.

June 2012

Chai X, Dage JL, and Citron M

Constitutive Secretion of Tau Protein by an Unconventional Mechanism

Neurobiol Dis 48(3):356-66

Publication Date: June 2, 2012

Product Type: iCell GABANeurons

Summary:

This study was designed to elucidate the mechanism(s) of tau processing and cellular trafficking, the dysregulation of which is a hallmark of Alzheimer’s disease and other tauopathies. iCell Neurons were shown to release a small percentage of intracellular tau by a nonconventional pathway that correlates with tau levels observed in vivo.

Impact:

iCell Neurons provided a biologically relevant human cell model to study the protein tau, which plays an important role in the development of Alzheimer’s disease and other neurodegenerative disorders. iCell Neurons provided significant advantages over other available model systems including transformed cell lines and primary neurons in intact animals.

April 2012

Phillips MJ, Wallace KA, Dickerson SJ, Miller MJ, Verhoeven AD, Martin JM, Wright LS, Shen W, Capowski EE, Percin EF, Perez ET, Zhong X, Canto-Soler MV, and Gamm DM

Blood-derived Human iPS Cells Generate Optic Vesicle-like Structures with the Capacity to Form Retinal Laminae and Develop Synapses

Invest Ophthalmol Vis Sci 53(4):2007-19

Publication Date: April 18, 2012

Product Type: iCell GABANeurons,

Summary:

MyCell iPS Cells were used to generate optical vesicle-like structures that have the capacity to self-assemble into rudimentary neuroretinal structures that express markers indicative of chemical and electrical synapses.

Impact:

MyCell iPS Cells were differentiated into retinal cell types and structures that can be used for disease modeling and early investigational studies toward the application of iPS cells for future regenerative medicine applications.

January 2012

Whitemarsh RC, Strathman MJ, Chase LG, Stankewicz C, Tepp WH, Johnson EA, and Pellett S

Novel Application of Human Neurons Derived from Induced Pluripotent Stem Cells for Highly Sensitive Botulinum Neurotoxin Detection

Toxicol Sci 126(2):426-35

Publication Date: January 5, 2012

Product Type: iCell GABANeurons

Summary:

iCell Neurons were identified as a functionally relevant human model to detect and study Clostridium botulinum neurotoxin (BoNT). Compared with primary rat spinal cord cells, iCell Neurons showed equal or increased sensitivity, improved dose-response, and more complete SNARE protein cleavage in response to BoNT treatment.

Impact:

iCell Neurons are rapidly being adopted by academic researchers to study mechanisms of BoNT toxicity, as well as by BoNT manufacturers to detect and measure BoNT potency.