Activity-dependent gene therapy for epilepsy
Abstract number :
1.459
Submission category :
2. Translational Research / 2B. Devices, Technologies, Stem Cells
Year :
2022
Submission ID :
2233023
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:29 AM
Authors :
Yichen Qiu, PhD – UCL Queen Square Institute of Neurology; Nathanael O'Neill, PhD – University College London; Benito Maffei, PhD – University College London; Clara Zourray, PhD – University College London; Amanda Almacellas-Barbanoj, PhD – University College London; Jenna Carpenter, PhD – University College London; Steffan Pettengell Jones, PhD – Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London; Marco Pinto Leite, PhD – University College London; Thomas Turner, PhD – University College London; Francisco Martins De Carvalho Moreira, PhD – University College London; Albert Snowball, PhD – University College London; Tawfeeq Shekh-Ahmad, PhD – Hebrew University School of Pharmacy; Vincent Magloire, PhD – University College London; Serena Barral, PhD – University College London; Manju Kurian, PhD – University College London; Matthew Walker, PhD; MD – University College London; Stephanie Schorge, PhD – University College London; Dimitri Kullmann, PhD; MD – University College London; Gabriele Lignani, PhD – University College London
This is a Late-Breaking abstract.
Rationale: Epilepsy remains one of the commonest serious neurological diseases. Thirty percent of people with epilepsy are refractory to pharmacological treatment, and surgical resection of the focal brain area remains the best option. Gene therapy is currently the most promising candidate replacement for surgical treatment of pharmaco-resistant focal epilepsy. However, current experimental gene therapies do not discriminate between neurons involved in seizure generation and ‘healthy’ surrounding neurons. Here, we use activity-dependent promoters to drive a therapeutic transgene that attenuates neuronal excitability only in pathologic hyperactive neurons. Once seizures resolve, the gene therapy tool automatically turns off. Self-time-limited expression of the transgene and specificity for over-active neurons argue that the treatment should be better tolerated.
Methods: We initially tested different immediate early genes (IEG) driving either the potassium channels KCNA1 or KCNJ2, invitro (using MEA) and ex vivo (using patch-clamp). Then, as proof-of-principle, we used the promoter of an extensively characterised IEGs, cfos, to drive the expression of KCNA1 in an animal model of intractable epilepsy. We also performed behaviour experiments to assess the effect of our innovative treatment on memory and learning. Furthermore, the gene therapy was then tested in a hyperexcitability model with cortical assembloids derived from human iPSCs.
Results: In vitro results showed that activity-dependent gene therapy is efficient in decreasing neuronal activity using different combinations of promoters and transgenes. In vivo results showed that cfos-KCNA1reduces network activity and seizures in a mouse model of intractable epilepsy (intra-amygdala kainate). Furthermore, our data shows that the activity-dependent gene therapy is self-regulated, it is switched-off when seizures were fully rescued. We also observed no behaviour deficits with mice treated with the activity-dependent gene therapy. In vivo testing of other promoter-transgene combinations is ongoing with encouraging preliminary results. Furthermore, we demonstrated that this gene therapy leads to fewer epileptiform activities when applied to neurons in patient derived organoids.
Conclusions: Activity-dependent gene therapy is a very promising innovative approach for the treatment of intractable epilepsy with great potential for translation into clinic in the near future.
Funding: Medical Research Council, Wellcome Trust, Sir Jules Thorn Charitable Trust, Epilepsy Research UK, NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Technology Funds
Translational Research