On-demand cell-autonomous gene therapy for brain circuit disorders

Qiu, Yichen; O’Neill, Nathanael; Maffei, Benito; Zourray, Clara; Almacellas-Barbanoj, Amanda; Carpenter, Jenna C.; Jones, Steffan P.; Leite, Marco; Turner, T. J.; Moreira, Francisco C.; Snowball, Albert; Shekh‐Ahmad, Tawfeeq; Magloire, Vincent; Barral, Serena; Kurian, Manju A.; Walker, Matthew C.; Schorge, Stephanie; Kullmann, Dimitri M.; Lignani, Gabriele

doi:10.1126/science.abq6656

Cited by 52 publications

(29 citation statements)

References 76 publications

(79 reference statements)

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“…Such strategies include different types of neurostimulation, surgical approaches, dietary treatments, gene therapy, antisense oligonucleotide therapy (ASO), and neurotransplantation, some of which may even cure epilepsy [238][239][240][241][242]. A recent fascinating example of how animal models can be used to develop such strategies is a genetic closed-loop feedback system in mice that was designed to inhibit neurons that participate in seizure activity [243]. To do this, Qiu et al [243] developed a genetic strategy based on the Fos gene, whose expression is up-regulated by neuronal activity, including seizures.…”

Section: The Use Of Animal Models As Tools For Developing Novel Non-p...mentioning

confidence: 99%

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Löscher

White

2023

Cells

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In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into the market for the treatment of epilepsy using well-established preclinical seizure and epilepsy models. Despite this success, approximately 20–30% of patients with epilepsy have drug-resistant epilepsy (DRE). The current approach to ASM discovery for DRE relies largely on drug testing in various preclinical model systems that display varying degrees of ASM drug resistance. In recent years, attempts have been made to include more etiologically relevant models in the preclinical evaluation of a new investigational drug. Such models have played an important role in advancing a greater understanding of DRE at a mechanistic level and for hypothesis testing as new experimental evidence becomes available. This review provides a critical discussion of the pharmacology of models of adult focal epilepsy that allow for the selection of ASM responders and nonresponders and those models that display a pharmacoresistance per se to two or more ASMs. In addition, the pharmacology of animal models of major genetic epilepsies is discussed. Importantly, in addition to testing chemical compounds, several of the models discussed here can be used to evaluate other potential therapies for epilepsy such as neurostimulation, dietary treatments, gene therapy, or cell transplantation. This review also discusses the challenges associated with identifying novel therapies in the absence of a greater understanding of the mechanisms that contribute to DRE. Finally, this review discusses the lessons learned from the profile of the recently approved highly efficacious and broad-spectrum ASM cenobamate.

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Section: The Use Of Animal Models As Tools For Developing Novel Non-p...mentioning

confidence: 99%

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Löscher

White

2023

Cells

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“…As mentioned above, anti-seizure treatment using EKC (or upregulating endogenous Kcna1 transcription) has been previously reported in models of temporal lobe epilepsy 15,16 . The present study adds FCD II to the range of epilepsy models in which gene therapy with CAMK2A-EKC is effective.…”

Section: Discussionmentioning

confidence: 86%

“…Overexpression of the voltage gated potassium channel Kv1.1, encoded by KCNA1 , leads to a moderate decrease in neuronal excitability and neurotransmitter release from axonal terminals 12 . Consequently, it has been validated as an effective gene therapy in several rodent models of focal epilepsy (focal neocortical epilepsy 13 and temporal lobe epilepsy 14,15 ), without off-target effects on a range of behaviours. Robust reductions in seizure frequency and/or duration were achieved by overexpressing wild type KCNA1 or an engineered version that bypasses the normal post-transcriptional editing of KCNA1 mRNA and reduces inactivation (engineered potassium channel, or EKC) 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Robust reductions in seizure frequency and/or duration were achieved by overexpressing wild type KCNA1 or an engineered version that bypasses the normal post-transcriptional editing of KCNA1 mRNA and reduces inactivation (engineered potassium channel, or EKC) 14 . An anti-epileptic effect has also been demonstrated by CRISPR-mediated upregulation of the endogenous murine Kcna1 gene 16 , and recently by using activity-dependent promoters to drive EKC 15 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-seizure Gene Therapy for Focal Cortical Dysplasia

Barbanoj

Graham

Maffei

et al. 2023

Preprint

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Focal Cortical Dysplasias (FCDs) are a common subtype of malformation of cortical development, which frequently present with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. FCD type II is typically caused by somatic mutations resulting in mTOR hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe FCD. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established FCD model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human RHEB plasmid, an activator of mTOR Complex 1. First, we further characterised this by quantifying electrocorticograms and behavioural abnormalities, both in mice developing spontaneous generalised seizures and in mice only exhibiting abnormal interictal discharges. Then, using continuous video-electrocorticogram recordings from epileptic mice before and after injection of AAV9-CAMK2A-EKC in the dysplastic region, we observed a robust decrease in the frequency of seizures and in interictal activity, compared to mice injected with a control viral vector. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal activity or behaviour in non-epileptic mice. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

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Gene Electrotransfer via Conductivity‐Clamped Electric Field Focusing Pivots Sensori‐Motor DNA Therapeutics: “A Spoonful of Sugar Helps the Medicine Go Down”

Pinyon,

von Jonquieres,

Crawford

et al. 2024

Advanced Science

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Viral vectors and lipofection‐based gene therapies have dispersion‐dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close‐field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of “naked” plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near‐field conductivity (“conductivity‐clamping”–CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic‐ready bionics‐derived CC‐GET device achieved neurotrophin‐encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics‐based hearing. The performance of CC‐GET is evaluated in the brain, an organ problematic for pulsed electric field‐based plasmid DNA delivery, due to high required currents causing Joule‐heating and damaging electroporation. Here CC‐GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red‐shifted channelrhodopsin and a genetically‐encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

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On-demand cell-autonomous gene therapy for brain circuit disorders

Cited by 52 publications

References 76 publications

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Anti-seizure Gene Therapy for Focal Cortical Dysplasia

Gene Electrotransfer via Conductivity‐Clamped Electric Field Focusing Pivots Sensori‐Motor DNA Therapeutics: “A Spoonful of Sugar Helps the Medicine Go Down”

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