Gene therapy for refractory epilepsy
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Epilepsy is the commonest serious neurological disorder, affecting approximately 1% of the population. People with active epilepsy have seriously disrupted lives. They cannot drive, experience social exclusion, have a high rate of depression and suicide, and are at risk of injury and even death during a seizure. About one quarter of people with epilepsy have seizures which are not prevented by any available medicines. In many cases, epilepsy is so disruptive that affected individuals are willing to undergo surgery to remove parts of their brains that generate seizures. Even this option is only open to relatively few people where the seizure-generating region is far from brain centres that control movement, language, vision and other essential functions. Most people with drug-resistant epilepsy have no realistic treatment options.
The main limitation to developing new medicines to treat epilepsy is that drugs taken as tablets affect nerve cells (neurons) throughout the brain, not just in the region responsible for triggering seizures. This results in side effects such as slowed thought processes, dizziness and altered mood, which prevent higher, potentially more effective, doses from being used. Moreover, most drugs used in epilepsy target similar mechanisms. There is an urgent need for new treatments that work in completely different ways.
We believe that we have found such a treatment that could be effective in a substantial proportion of people in whom seizures arise from an identifiable brain region. Instead of using drugs, we are adding a gene to a small number of neurons that are involved in seizure generation to make them less excitable, so preventing seizures from occurring.
Why should we undertake this work? We are a group of basic scientists and clinicians with in-depth knowledge of how neurons change as epilepsy develops, and how genes interact to make neurons more or less active. We have worked together for several years to develop a gene therapy that works in epilepsy. We identified an experimental model of epilepsy that is particularly difficult to treat, which resembles that seen in many people who are currently without effective treatment. We also worked with a collaborator in the USA to develop new ways of monitoring seizures automatically. Our results are very encouraging: not only does our treatment stop epilepsy from developing, but it also progressively stops seizures when epilepsy is already established. In essence, our treatment can 'cure' epilepsy, which has never been demonstrated previously. This is in spite of the fact that our treatment only targets a relatively small number of neurons. Gene therapy did not completely stop neurons from firing, and had no detectable side effects, and yet it completely prevented seizures.
Although our work received considerable media interest, we are not yet ready to start clinical trials. We have only tried one experimental model of epilepsy, and only using two different genes. To maximise the prospects for success in clinical trials, we need to improve our understanding of how our treatment works, ensure that we are using the best gene therapy tools, and test them in different situations. We will compare several different ways of calming neurons, and different ways of delivering the gene therapy. We will also test ways of switching on and off the calming effect on the neurons by using gene therapy that makes a small number of neurons sensitive to a drug that is normally inactive in the brain, or that allows brief pulses of light shone into the brain to stop selected neurons firing. We will put our gene therapy through a series of increasingly stringent tests, and look closely for any possible side effects.
By the end of our programme, complemented by safety studies, we aim to be ready to start clinical trials, raising hope for tens of thousands of people in the UK, and millions around the world, who currently suffer from uncontrolled seizures.
The main limitation to developing new medicines to treat epilepsy is that drugs taken as tablets affect nerve cells (neurons) throughout the brain, not just in the region responsible for triggering seizures. This results in side effects such as slowed thought processes, dizziness and altered mood, which prevent higher, potentially more effective, doses from being used. Moreover, most drugs used in epilepsy target similar mechanisms. There is an urgent need for new treatments that work in completely different ways.
We believe that we have found such a treatment that could be effective in a substantial proportion of people in whom seizures arise from an identifiable brain region. Instead of using drugs, we are adding a gene to a small number of neurons that are involved in seizure generation to make them less excitable, so preventing seizures from occurring.
Why should we undertake this work? We are a group of basic scientists and clinicians with in-depth knowledge of how neurons change as epilepsy develops, and how genes interact to make neurons more or less active. We have worked together for several years to develop a gene therapy that works in epilepsy. We identified an experimental model of epilepsy that is particularly difficult to treat, which resembles that seen in many people who are currently without effective treatment. We also worked with a collaborator in the USA to develop new ways of monitoring seizures automatically. Our results are very encouraging: not only does our treatment stop epilepsy from developing, but it also progressively stops seizures when epilepsy is already established. In essence, our treatment can 'cure' epilepsy, which has never been demonstrated previously. This is in spite of the fact that our treatment only targets a relatively small number of neurons. Gene therapy did not completely stop neurons from firing, and had no detectable side effects, and yet it completely prevented seizures.
Although our work received considerable media interest, we are not yet ready to start clinical trials. We have only tried one experimental model of epilepsy, and only using two different genes. To maximise the prospects for success in clinical trials, we need to improve our understanding of how our treatment works, ensure that we are using the best gene therapy tools, and test them in different situations. We will compare several different ways of calming neurons, and different ways of delivering the gene therapy. We will also test ways of switching on and off the calming effect on the neurons by using gene therapy that makes a small number of neurons sensitive to a drug that is normally inactive in the brain, or that allows brief pulses of light shone into the brain to stop selected neurons firing. We will put our gene therapy through a series of increasingly stringent tests, and look closely for any possible side effects.
By the end of our programme, complemented by safety studies, we aim to be ready to start clinical trials, raising hope for tens of thousands of people in the UK, and millions around the world, who currently suffer from uncontrolled seizures.
Technical Summary
Our proposal builds upon our recent breakthroughs in preventing epileptogenesis and treating established epilepsy with gene therapy using lentiviral overexpression of the potassium channel Kv1.1 and the optogenetic inhibitor halorhodopsin. We will determine which gene therapy tools are most effective for suppressing seizures and which are best tolerated. This involves testing a carefully selected series of different channels (Kv1.1, Kir2.1, Kv7.2/3; synthetic receptors, and improved opsins), promoters (inducible and cell specific), and vectors for delivery (non-integrating, and AAV). We will investigate how well the evolution of focal seizures in our models maps onto human disease and how they are disrupted by gene therapy. We will also push to expand the therapeutic potential by testing our best candidates in additional models of focal epilepsy (visual cortex induced by tetanus toxin, ferric chloride and cobalt), limbic epilepsy, and generalised epilepsy. Much of our work is aimed at identifying the optimal strategy that can lead to clinical trials in patients with refractory epilepsy, but we will seek separate funding to perform toxicology studies and meet the regulatory requirements in preparation for such trials.
This is a revision of a highly ranked proposal entitled 'Viral manipulation of brain excitability for treatment of epilepsy' (September 2012), which received very positive evaluations but was criticised by two reviewers for focusing mainly on focal neocortical epilepsy with less attention to temporal lobe epilepsy. Focal neocortical epilepsy actually represents a greater unmet need than TLE, which can in many cases be treated by surgery. We recently audited our epilepsy practice and confirmed that 56% of patients referred for consideration of surgery had neocortical epilepsy. We have included pilot data acquired since the first submission and made further alterations and clarifications to address other points in the Case for Support.
This is a revision of a highly ranked proposal entitled 'Viral manipulation of brain excitability for treatment of epilepsy' (September 2012), which received very positive evaluations but was criticised by two reviewers for focusing mainly on focal neocortical epilepsy with less attention to temporal lobe epilepsy. Focal neocortical epilepsy actually represents a greater unmet need than TLE, which can in many cases be treated by surgery. We recently audited our epilepsy practice and confirmed that 56% of patients referred for consideration of surgery had neocortical epilepsy. We have included pilot data acquired since the first submission and made further alterations and clarifications to address other points in the Case for Support.
Planned Impact
The potential to have an impact: Approximately 1% of the population is affected by epilepsy, of whom over 20% continue to have seizures despite optimal pharmacotherapy. Further refinements in small molecule antiepileptic drugs are unlikely to alter this statistic. Surgery is only feasible in a small proportion of patients. Approximately 150,000 people in the UK have no realistic treatment options, and continue to have seizures, and experience major co-morbidities and social exclusion. The annual risk of sudden unexpected death in refractory epilepsy is around 2%, with a cumulative life-time risk between 7 and 40%. The annual cost of epilepsy to the European Union was estimated at Euro 15.5 billion (2004). The treatment gap is immense, and epilepsy research is underfunded in comparison to diseases of comparable impact. Per patient, Parkinson's disease and multiple sclerosis research receive 7 times more funding from the NIH (Meador, Neurology 2011).
Potential clinical impact: Of the advanced treatments that have been contemplated in refractory epilepsy gene therapy is the most likely to reach clinical trials, because the vectors have been refined and tested in other disorders. Our work to date has identified a highly effective and well tolerated treatment that could be translated to clinical trials. However, the aim of this proposal is to explore different refinements to the gene therapy tool, and test their applicability to different forms of focal epilepsy. This will form the scientific basis for clinical trials, which we anticipate can begin in 5-10 years.
Potential patient impact: A successful outcome of clinical trials could have a major impact on the quality of life of people with refractory epilepsy. Indeed, gene therapy, if successful could even be offered to people who are currently candidates for surgical resection. If the gene therapy is unsuccessful they could still proceed to resection (which would remove the transduced region and allow it to be studied with electrophysiological and other methods). If, on the other hand, the gene therapy is successful it would spare patients from a major irreversible surgical procedure with considerable risks to cognitive, sensory or motor function.
Neuroscience research: A safe and effective method of regulating the excitability of targeted neurons is a tool that will be important for neuroscience research as well as being applicable to other neurological and psychiatric conditions. The EEG monitoring system has already been applied in other research areas and the EEG analysis methods are being used in human EEG.
The wider public: there is a strong interest in treating the most resistant forms of epilepsy, and as this disease is common, a large proportion of the public will know someone with epilepsy. An entirely new route to treatment will have an impact on many families.
Timescales: During the course of the project we will present data at charities and symposia that will reach our academic and clinical beneficiaries. Our major publications will fall towards the end of the project, by which time we anticipate that our findings will be informing other studies of gene therapy tools in epilepsy. We are actively investigating strategies for increasing clinical translation, and we are already investigating pre-clinical studies to move our gene therapy tools into phase I/II trials.
Skills for staff on project: The staff will gain advanced skills in in vivo and in vitro electrophysiology (including patch clamp), viral manipulation, and models of epilepsy. Skilled electrophysiologists are in high demand; thus we anticipate that researchers hired on this project will be competitive for future positions.
In summary, the beneficiaries of the research are people with epilepsy, society as a whole because of the size of the economic impact of the disease, and other researchers who can tap into the technical developments that we are supporting.
Potential clinical impact: Of the advanced treatments that have been contemplated in refractory epilepsy gene therapy is the most likely to reach clinical trials, because the vectors have been refined and tested in other disorders. Our work to date has identified a highly effective and well tolerated treatment that could be translated to clinical trials. However, the aim of this proposal is to explore different refinements to the gene therapy tool, and test their applicability to different forms of focal epilepsy. This will form the scientific basis for clinical trials, which we anticipate can begin in 5-10 years.
Potential patient impact: A successful outcome of clinical trials could have a major impact on the quality of life of people with refractory epilepsy. Indeed, gene therapy, if successful could even be offered to people who are currently candidates for surgical resection. If the gene therapy is unsuccessful they could still proceed to resection (which would remove the transduced region and allow it to be studied with electrophysiological and other methods). If, on the other hand, the gene therapy is successful it would spare patients from a major irreversible surgical procedure with considerable risks to cognitive, sensory or motor function.
Neuroscience research: A safe and effective method of regulating the excitability of targeted neurons is a tool that will be important for neuroscience research as well as being applicable to other neurological and psychiatric conditions. The EEG monitoring system has already been applied in other research areas and the EEG analysis methods are being used in human EEG.
The wider public: there is a strong interest in treating the most resistant forms of epilepsy, and as this disease is common, a large proportion of the public will know someone with epilepsy. An entirely new route to treatment will have an impact on many families.
Timescales: During the course of the project we will present data at charities and symposia that will reach our academic and clinical beneficiaries. Our major publications will fall towards the end of the project, by which time we anticipate that our findings will be informing other studies of gene therapy tools in epilepsy. We are actively investigating strategies for increasing clinical translation, and we are already investigating pre-clinical studies to move our gene therapy tools into phase I/II trials.
Skills for staff on project: The staff will gain advanced skills in in vivo and in vitro electrophysiology (including patch clamp), viral manipulation, and models of epilepsy. Skilled electrophysiologists are in high demand; thus we anticipate that researchers hired on this project will be competitive for future positions.
In summary, the beneficiaries of the research are people with epilepsy, society as a whole because of the size of the economic impact of the disease, and other researchers who can tap into the technical developments that we are supporting.
Publications
Nicholson E
(2014)
Long-term potentiation in hippocampal oriens interneurons: postsynaptic induction, presynaptic expression and evaluation of candidate retrograde factors.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Mantoan Ritter L
(2016)
Lentiviral expression of GAD67 and CCK promoter-driven opsins to target interneurons in vitro and in vivo.
in The journal of gene medicine
Spillane J
(2015)
Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels.
in Neurology
Vivekananda U
(2017)
Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization.
in Proceedings of the National Academy of Sciences of the United States of America
Bygrave A
(2016)
Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801
in Translational Psychiatry
Magloire V
(2019)
KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition.
in Nature communications
Le Duigou C
(2015)
Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Tomlinson SE
(2016)
In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.
in Brain : a journal of neurology
Colasante G
(2020)
In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy.
in Brain : a journal of neurology
Description | A Network Approach to Gene Therapy for Refractory Epilepsies |
Amount | £2,640,411 (GBP) |
Funding ID | MR/V034758/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2021 |
End | 09/2026 |
Description | AMPA Receptor Mutations are Important Causes of Epilepsy, Autism Spectrum and Developmental Disorders |
Amount | £196,734 (GBP) |
Funding ID | V4619 |
Organisation | Great Ormond Street Hospital Children's Charity (GOSHCC) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2024 |
Description | AMR/LifeArc "Over 36 months for the following project: Repurposing gene therapy for children with refractory epilepsy due to malformations of cortical development." |
Amount | £247,521 (GBP) |
Funding ID | GN2930 |
Organisation | Action Medical Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2023 |
End | 02/2026 |
Description | DREADDs for clinical translation |
Amount | £4,773,609 (GBP) |
Funding ID | MR/W005204/1 |
Organisation | University College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2022 |
End | 07/2024 |
Description | Engineered Potassium Channel gene therapy for epilepsy |
Amount | £2,488,648 (GBP) |
Funding ID | MR/R015333/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 12/2024 |
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 | 03/2018 |
End | 04/2022 |
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 | 03/2019 |
End | 03/2021 |
Description | Gene therapy for epilepsy & focal cortical dysplasia |
Amount | £190,404 (GBP) |
Funding ID | V4019 |
Organisation | Great Ormond Street Hospital Children's Charity (GOSHCC) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2021 |
Description | Glutamate-gated chloride channel treatment of epilepsy |
Amount | £456,266 (GBP) |
Funding ID | 209807 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 10/2020 |
Description | 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 | 09/2018 |
End | 12/2021 |
Description | How does cortical spreading depression relate to seizures? |
Amount | £149,931 (GBP) |
Funding ID | P1806 |
Organisation | Epilepsy Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2018 |
End | 08/2020 |
Description | In utero electroporation training - Dr Gabriele Lignani and Dr Vincent Magloire |
Amount | £1,316 (GBP) |
Funding ID | MRF-007-0004-STD-KULLM |
Organisation | Medical Research Council (MRC) |
Department | Medical Research Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 07/2019 |
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 | 09/2018 |
End | 09/2020 |
Description | Investigator Award: Synaptic Neurology |
Amount | £1,500,000 (GBP) |
Funding ID | 212285/Z/18/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2023 |
Description | Neurotransmitter imaging to understand seizure mechanisms |
Amount | £663,250 (GBP) |
Funding ID | MR/V013556/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2021 |
End | 03/2024 |
Description | Programme grant: Gene therapy for refractory epilepsy |
Amount | £3,100,000 (GBP) |
Funding ID | MR/L01095X/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2014 |
End | 07/2019 |
Description | Strategic Award "Synaptopathies" |
Amount | £4,000,000 (GBP) |
Funding ID | WT104033AIA |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
End | 04/2020 |
Description | Strategic Grant on Synaptopathies |
Amount | £4,200,000 (GBP) |
Funding ID | WT104033AIA |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
End | 03/2020 |
Description | Synaptic Neurology |
Amount | £1,600,865 (GBP) |
Funding ID | 212285/Z/18/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 10/2024 |
Description | Synaptic Neurology |
Amount | £1,600,865 (GBP) |
Funding ID | 212285 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 10/2023 |
Description | Synaptopathies: genetics, biophysics and circuit mechanisms of paroxysmal neurological disorders. |
Amount | £4,194,451 (GBP) |
Funding ID | 104033 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
End | 04/2020 |
Description | Synaptopathies: genetics, biophysics and circuit mechanisms of paroxysmal neurological disorders. |
Amount | £4,194,451 (GBP) |
Funding ID | 104033/Z/14/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
End | 03/2022 |
Description | The role of parvalbumin-positive interneurons in the generation of epileptiform discharges in vivo. |
Amount | £149,947 (GBP) |
Funding ID | P1702 |
Organisation | Epilepsy Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2017 |
End | 06/2019 |
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 |
Description | School of Pharmacy |
Organisation | University College London |
Department | School of Pharmacy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mouse mutants |
Collaborator Contribution | Expertise in ion channel recordings from presynaptic boutons |
Impact | Joint publication |
Start Year | 2009 |
Description | Synaps study group |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration on neurogenetics especially relevant to synaptopathies |
Collaborator Contribution | New insights from human mutations associated with neurological diseases |
Impact | papers resulting from this collaboration are listed under publications |
Start Year | 2015 |
Description | Various collaborators at the Institute of Neurology |
Organisation | University College London |
Department | Institute of Neurology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | viral methods, clinical genetics, epilepsy models |
Collaborator Contribution | many methodological collaborations |
Impact | numerous papers, grants |
Title | ACTIVITY-DEPENDENT GENE THERAPY FOR NEUROLOGICAL DISORDERS |
Description | The invention provides expression vectors or vector systems comprising a polynucleotide sequence encoding a polypeptide, wherein the gene is operably linked to a neuronal activity-dependent promoter suitable to drive expression of the gene product in a subject's neural cells. The features of the expression vectors combine to advantageously improve the treatment of a neurological disorder associated with neuronal hyperexcitability in a subject. The invention also provides the expression vectors or vector systems for use in related methods of treatment, as well as viral particles, cells, kits and methods using the expression vectors or vector systems. |
IP Reference | WO2021191474 |
Protection | Patent application published |
Year Protection Granted | 2021 |
Licensed | No |
Impact | This provides a novel approach to treat epilepsy. A spinout company with a licence to the patent is in the process of being created, with seed capital from the UCL Technology Fund, |
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 | 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 | US2019134155 |
Protection | Patent granted |
Year Protection Granted | 2019 |
Licensed | No |
Impact | Looking for commercial partner to carry out trial in human epilepsy |
Title | Chloride channels and uses thereof |
Description | A chimeric glutamate-gated chloride channel that can be delivered using an AAV for the treatment of epilepsy |
IP Reference | 2401492.0 |
Protection | Patent / Patent application |
Year Protection Granted | |
Licensed | No |
Impact | This provides a refinement to a tool previously reported in Lieb et al (2019) |
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 | We are progressing to a clinical trial with funding from MRC DPFS |
Title | Endogenous gene regulation to treat neurological disorders and diseases |
Description | Use of CRISPR-activation to upregulate endogenous gene expression to treat neurological disorders and diseases |
IP Reference | |
Protection | Patent / Patent application |
Year Protection Granted | 2022 |
Licensed | No |
Impact | This invention has led to translational funding from the UCL Technology Fund |
Title | SYNTHETIC RECEPTORS |
Description | The invention relates to modified G-protein coupled receptors (GPCRs) which (i) have decreased responsiveness to an endogenous activating ligand, and (ii) may be activated by exogenous agonists, which may be relatively benign over the counter drugs such as antihistamines. The modifications comprise mutations at particular amino acid positions, relative to the unmodified GPCRs. The invention also provides methods of use comprising administration of the modified GPCRs, for example in treating a neurological circuit disorder. |
IP Reference | WO2022238513 |
Protection | Patent / Patent application |
Year Protection Granted | 2022 |
Licensed | No |
Impact | This overcomes limitations of DREADDs and is potentially amenable to clinical translation. |
Title | TREATMENT OF ACQUIRED FOCAL EPILEPSY |
Description | The invention provides methods of treatment of acquired focal epilepsy in a human subject in need of the same, the methods comprising: (i) providing an expression vector encoding a polynucleotide sequence encoding LGI1, wherein the polynucleotide sequence is operably linked to a promoter suitable to drive expression of the LGI1 in human cells, (ii) administering the expression vector to the subject. Overexpressing LGI1 has been shown to affect excitatory neurons beyond the area of expression thereby targeting a large area and affecting neurons in an advantageously uniform manner. |
IP Reference | WO2023152318 |
Protection | Patent / Patent application |
Year Protection Granted | 2023 |
Licensed | No |
Impact | This represents a unique mechanism of action by which the transgene encodes a diffusible protein that reduces circuit excitability |
Company Name | Epilepsygtx |
Description | Epilepsygtx develops gene therapy for refractory epilepsy. |
Year Established | 2021 |
Impact | The company is just set up. The impact will be to consolidate a portfolio of gene therapy approaches to treat refractory epilepsy and to deliver clinical trails. |
Company Name | Epilepsygtx |
Description | Epilepsygtx develops gene therapy for refractory epilepsy. |
Year Established | 2021 |
Impact | The company has supported CTA-enabling toxicity, biodistribution and efficacy studies, and is in the process of raising a Series A investment to commission manufacture of a batch of clinical grade viral vector and submit a CTA application. |