Using Patient-Derived Induced Pluripotent Stem Cells to Model and Treat Epilepsies

Du, Xixi; Parent, Jack M.

doi:10.1007/s11910-015-0588-3

Cited by 33 publications

(18 citation statements)

References 76 publications

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“…These new technologies have been widely applied in human neurological and cardiac diseases, where patient-specific iPSC lines act as powerful tools as in vitro disease models [34][35][36]. These include new gene therapy strategies for iPSC-dervied cellular models of hypertrophic cardiomyopathy [37].…”

Section: Discussionmentioning

confidence: 99%

Inducing Pluripotency in the Domestic Cat (Felis catus)

Dutton

Dudhia

Guest

et al. 2019

Stem Cells and Development

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Domestic cats suffer from a range of inherited genetic diseases, many of which display similarities with equivalent human conditions. Developing cellular models for these inherited diseases would enable drug discovery, benefiting feline health and welfare as well as enhancing the potential of cats as relevant animal models for translation to human medicine. Advances in our understanding of these diseases at the cellular level have come from the use of induced pluripotent stem cells (iPSCs). iPSCs are capable of differentiating into derivatives of all three germ layers, therefore overcoming the limitations of primary differentiated cells and the ethical concerns of using embryonic stem cells. No studies however report the generation of iPSCs from domestic cats (fiPSCs). Feline adipose derived fibroblasts were infected with amphotropic retrovirus containing the coding sequences for human Oct4, Sox2, Klf4, cMyc and Nanog. Isolated iPSC clones were expanded on mouse inactivated embryonic fibroblasts in the presence of feline leukaemia inhibitory factor (LIF). Retroviral delivery of human pluripotent genes gave rise to putative fiPSC colonies within 5-7 days. These iPS-like cells required foetal bovine serum and feline LIF for maintenance. Colonies were domed with refractile edges, similar to mouse iPSCs. Immunocytochemistry demonstrated positive staining for stem cell markers: alkaline phosphatase, Oct4, Sox2, Nanog and SSEA1. Cells were negative for SSEA4. Expression of endogenous feline Nanog was confirmed by qPCR. The cells were able to differentiate in vitro into cells representative of the three germ layers. These results confirm the generation of the first induced pluripotent cells from domestic cats. These cells will provide valuable models to study genetic diseases and explore novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Inducing Pluripotency in the Domestic Cat (Felis catus)

Dutton

Dudhia

Guest

et al. 2019

Stem Cells and Development

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“…Furthermore, for efficacy testing of novel molecular targeting approaches, animal models may not be that relevant because of major species differences in the target molecules and the need for specific modulators (e.g., targeting of species-specific regulatory RNAs). Here, the use of patient-derived iPSCs and other novel approaches, such as genetically engineered zebrafish and mouse models, may be of value (Baraban and Löscher, 2014;Du and Parent, 2015;Grone and Baraban, 2015;Parent and Anderson, 2015;Demarest and Brooks-Kayal, 2018). This, for instance, concerns the targeting of the natural antisense transcript (NAT) class of long noncoding RNAs by antagoNAT oligonucleotides, which can be designed to inhibit cis-acting lncRNA, thereby increasing the expression of a selected protein.…”

Section: A Development Of New Antiseizure Drugs By Using New Drug-scmentioning

confidence: 99%

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

et al. 2020

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Significance Statement-Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome. 608 Löscher et al. Adapted from Rogawski and Löscher (2004), Rogawski et al. (2016), and Sills and Rogawski (2020) Molecular target ASDs that act on target Voltage-gated ion channels Voltage-gated sodium channels Phenytoin, fosphenytoin, a carbamazepine, oxcarbazepine, b eslicarbazepine acetate, c lamotrigine, lacosamide; possibly topiramate, zonisamide, rufinamide Voltage-gated calcium channels (T-type) Ethosuximide Voltage-gated potassium channels (K v 7) Retigabine (ezogabine) GABA-mediated inhibition GABA A receptors Phenobarbital, primidone, stiripentol, benzodiazepines, (including diazepam, lorazepam, midazolam and clonazepam), possibly topiramate, felbamate, retigabine (ezogabine) GAT1 GABA transporter Tiagabine GABA transaminase Vigabatrin Glutamic acid decarboxylase Possibly valproate, gabapentin, pregabalin Presynaptic release machinery SV2A Levetiracetam, brivaracetam a2d subunit of calcium channels Gabapentin, pregabalin Ionotropic glutamate receptors AMPA receptor Perampanel Carbonic anhydratase inhibition Acetazolamide, topiramate, zonisamide, possibly lacosamide Disease-specific mTORC1 signaling d Everolimus Lysosomal enzyme replacement e Cerliponase alfa (recombinant tripeptidyl peptidase 1) Mixed/unknown Valproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorticotrophin (ACTH), cannabidiol, cenobamate AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. a Fosphenytoin is a prodrug for phenytoin. b Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. c Eslicarbarbazepine acetate is a prodrug for S-licarbazepine. d In patients with epilepsy because of tuberous sclerosis complex (TSC). e In patients with epilepsy because of neuronal ceroid lipofuscinosis type 2.

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“…Although logical, there was a counterargument that many of the current epilepsy medications were based on drug testing in normal animals. Regardless, there is an increasing need for "high throughput" models such as zebrafish, 32 organotypic hippocampal cultures, 33 patient-derived stem cells, 34 and organoids. 35 Advances in computational models have also led to new ways to study epilepsy.…”

Section: Animal Models Of Epilepsymentioning

confidence: 99%

The Dentate Gyrus and Temporal Lobe Epilepsy: An “Exciting” Era

Scharfman

2019

Epilepsy Curr

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This review describes developments in epilepsy research during the last 3 to 4 decades that focused on the dentate gyrus (DG) and its role in temporal lobe epilepsy (TLE). The emphasis is on basic research in laboratory animals and is chronological, starting with hypotheses that attracted a lot of attention in the 1980s. Then experiments are described that addressed the questions, as well as new methods that often made the experiments possible. In addition, where new questions arose and the implications for clinical epilepsy are discussed.

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Using Patient-Derived Induced Pluripotent Stem Cells to Model and Treat Epilepsies

Cited by 33 publications

References 76 publications

Inducing Pluripotency in the Domestic Cat (Felis catus)

Inducing Pluripotency in the Domestic Cat (Felis catus)

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

The Dentate Gyrus and Temporal Lobe Epilepsy: An “Exciting” Era

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