Lentiviral potassium channel expression to treat focal neocortical epilepsy

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Epilepsy affects approximately 300,000 people in the UK, of whom about 100,000 do not respond to available medication. An especially severe form of drug-resistant epilepsy (focal neocortical epilepsy) often occurs when seizures arise from a small area of abnormal tissue in the brain. Because the rest of the brain is often intact, it should be possible to alter the excitability of neurons in the abnormal area to stop seizures arising or to terminate them when they occur. We have validated an experimental model of focal neocortical epilepsy and have done much ground-work to use modified viruses to change the expression of individual genes in neurons. We propose to reduce the excitability of neurons in the seizure focus, or alternatively to enhance the excitability of inhibitory neurons. Our work will build on preliminary data that we have obtained by studying the consequences of rare neurological disease caused by mutations of genes that encode ion channels, proteins that underlie the electrical signalling of individual neurons.

Technical Summary

Focal neocortical epilepsy is among the most difficult forms of epilepsy to treat: it is very often refractory to available drugs, and the seizure focus is amenable to surgical resection in only a minority of cases. We have previously validated an experimental model of this disorder, which recapitulates its main features including continuous or near-continuous seizure activity and resistance to drugs that are effective in other epilepsy models. The seizures do however respond to focal drug delivery, showing that this disease is, in principle, treatable with more targeted methods of altering the excitability of neurons. We will capitalise on our complementary expertise in epileptology, cellular biophysics and molecular biology to test novel therapeutic strategies based on viral delivery of K+ channels into the seizure focus. We will express Kv1.1 and Kir2.1 (which we have previously studied in the context of neurological channelopathies) to lower the excitability of neurons in the seizure focus and/or reduce neurotransmitter release from their terminals. In parallel, we will also use promoters that are active in interneurons to drive the expression of a dominant-negative K+ channel mutant in interneurons, in order to raise their excitability and enhance neurotransmitter release from their terminals. The effectiveness of these strategies will be monitored by taking advantage of a new wireless video-EEG rodent telemetry facility that we have established.

Publications

10 25 50

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Begum R (2016) Action potential broadening in a presynaptic channelopathy. in Nature communications

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Colasante G (2020) dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice. in Molecular therapy : the journal of the American Society of Gene Therapy

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Crisp SJ (2016) Autoimmune synaptopathies. in Nature reviews. Neuroscience

 
Description Appointed to Epilepsy Research UK Science Advisory Committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Appointed to board of Trustees for Epilepsy Research UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Member of SACGM(CU)
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Queen Square award for implemenation of 3Rs in Research
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact We are working to change our local attitudes towards working with animals in research. We presented this award to the then Cabinet Minister, and it was recognised as a high level local engagement with the 3Rs in animal work. All students presenting their scientific posters at the symposium are now aware that they must also explain their measures to improve 3Rs to our NACWO, including justifying the model used.
 
Description UCL Celebrates the 3Rs
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Engineered Potassium Channel gene therapy for epilepsy
Amount £2,200,000 (GBP)
Funding ID MR/R015333/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 04/2022
 
Description FP7 grant
Amount £300,000 (GBP)
Funding ID 602130 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 09/2013 
End 08/2018
 
Description GOSH/Sparks: Gene therapy for epilepsy & focal cortical dysplasia
Amount £190,404 (GBP)
Organisation Great Ormond Street Hospital (GOSH) 
Sector Hospitals
Country United Kingdom
Start 04/2019 
End 03/2021
 
Description Innovator Award: Glutamate-gated chloride channel treatment of epilepsy
Amount £456,266 (GBP)
Funding ID 209807/Z/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2020
 
Description MRC DPFS Award
Amount £2,200,000 (GBP)
Funding ID MR/R015333/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 03/2022
 
Description MRC Project Grant
Amount £400,000 (GBP)
Funding ID MR/L003457/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2014 
End 01/2017
 
Description ONO Pharmaceuticals Pilot funding
Amount £70,000 (GBP)
Organisation Ono Pharmaceutical 
Sector Private
Country Japan
Start 04/2017 
End 10/2017
 
Description Programme Grant
Amount £2,468,066 (GBP)
Funding ID MR/L01095X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2014 
End 07/2019
 
Description Wellcome Trust Investigaotr Award
Amount £2,400,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2018
 
Description OpenSourceInstruments 
Organisation Open Source Instruments
Country United States 
Sector Private 
PI Contribution We have entered into a highly successful collaboration with OpenSourceInstruments (K Hashemi) based at Brandeis University. This has led to the development of a wireless EEG telemetry system that has been adopted by several other groups around the world, including Dr Louise Upton at Oxford. The designs are freely accessible under the GNU open licence.
Collaborator Contribution Facility for improved EEG detection and analysis
Impact Extensive details available at http://www.opensourceinstruments.com/SCT/
Start Year 2009
 
Description SS and MCW 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution collaboration to develop new treatment for focal epilepsy
Collaborator Contribution Expertise in molecular biology and epilepsy models
Impact grants awarded
Start Year 2006
 
Title COMBINED USE OF A VECTOR ENCODING A MODIFIED RECEPTOR AND ITS EXOGENOUS AGONIST IN THE TREATMENT OF SEIZURES 
Description The invention provides methods and materials for treating a seizure disorder such as epilepsy in a patient which employ a vector encoding a modified receptor, the so-called "DREADD" receptor being characterised by (i) a decreased responsiveness to its endogenous activating ligand (ii) a retained or enhanced responsiveness to an exogenous agonist. The modified receptor is expressed in neurons of a seizure focus in brain of the patient, and an exogenous agonist is administered which activates the modified receptor to reversibly alters the excitability of the neurons in the seizure focus leading to synaptic silencing or other inhibition. 
IP Reference US2016375097 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact This licencing is part of a portfolio of approaches to developing gene therapy to treat epilepsy
 
Title COMBINED USE OF A VECTOR ENCODING A MODIFIED RECEPTOR AND ITS EXOGENOUS AGONIST IN THE TREATMENT OF SEIZURES 
Description The invention provides methods and materials for treating a seizure disorder such as epilepsy in a patient which employ a vector encoding a modified receptor, the so-called "DREADD" receptor being characterised by (i) a decreased responsiveness to its endogenous activating ligand (ii) a retained or enhanced responsiveness to an exogenous agonist. The modified receptor is expressed in neurons of a seizure focus in brain of the patient, and an exogenous agonist is administered which activates the modified receptor to reversibly alters the excitability of the neurons in the seizure focus leading to synaptic silencing or other inhibition. 
IP Reference WO2015136247 
Protection Patent application published
Year Protection Granted 2015
Licensed Yes
Impact We are seeking investment to take this to clinical trials
 
Title EXPRESSION VECTORS COMPRISING ENGINEERED GENES 
Description The invention provides expression vectors, nucleic acids, vector particles and methods of treatment involving these vector particles, comprising an engineered KCNA 1 gene encoding an edited Kv1.1 potassium channel, as well as methods of confirming the presence of engineered KCNA 1 mRNA in a cell. The features of the engineered KCNA 1 gene combine to advantageously enhance the translation and activity of the Kv1.1 protein and improve detection of KCNA 1 gene expression in a cell and can be used for example in the treatment of epilepsy and similar neurological disorders. 
IP Reference WO2018229254 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact This patent is helping support our award to translate our gene therapy to a first in human clinical trial
 
Company Name Sarentis 
Description Start-up founded by Dr Denise Barbut, New York 
Year Established 2015 
Impact Sarentis is currently seeking investment to take our gene therapy into clinical trials
 
Description DIS visits from students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact International undergraduate students (20-30) with the DIS programme in Copenhagen visit ION at Queen Square, hear a presentation and tour the Department, and discuss careers in science with the team.
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Pint of Science presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This was for general public with an audience of about 30.

Raised public profile of research via talk and website
Year(s) Of Engagement Activity 2013
 
Description Presentation at Royal Society summer science festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact I gave a presentation "Brain Hacking With Viruses" introducing the concepts of Gene therapy for epilepsy at the Royal Society Summer Science Festival. The talk was repeated 4 times, and was well attended by students from around the UK. I also raised some of the ethical and safety concerns of the approach and got very strong feedback in the questions that students were interested even if the testing involved use of animals in research.
Year(s) Of Engagement Activity 2016
URL https://royalsociety.org/science-events-and-lectures/2016/07/schools-talk-schorge-tuesday/
 
Description Royal Society Summer festival presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a summer science 'lates' which meant running a both with a hands on activity for people attending the Royal Society Summer Science Festival. We presented an origami hands-on demonstration of how gene therapy uses viral shells to carry instructions for making healthy genes. The event was very well attended with over 3000 at the Royal society, and my personal booth (going by how many sheets of origami paper we gave out) had over 100 visitors, mostly from the general public but also some schools and university students.
Year(s) Of Engagement Activity 2018
URL https://royalsociety.org/science-events-and-lectures/2018/07/summer-science-lates/
 
Description School Visit (Lenox) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact This was a presentation on Gene Therapy and treatments of epilepsy to a High School audience in the states.
Year(s) Of Engagement Activity 2016,2017
 
Description Work experience at ION 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Both students were well-engaged with basic and clinical research at the Institute of Neurology.

Social Mobility Fund and the Worshipful Company of Pewterers have both indicated they'd be delighted to carry on with the scheme in future years.
Year(s) Of Engagement Activity 2014