Gene therapy for epilepsy

Gene therapy is being studied for some forms of epilepsy . [1] It relates to viral or non-viral vectors to deliver DNA or RNA to target areas where seizures arise, or to reduce the frequency of seizures . Gene therapy HAS Delivered promising results in early stage clinical trials for other neurological disorders Such As Parkinson’s disease , [2] raising the Hope that it will Become a treatment for intractable epilepsy .

Overview

Epilepsy Refers to a group of chronic neurological disorders That are caractérisée by seizures , Affecting over 50 million people, or 0.4-1% of the overall population. [3] [4] There is a basic understanding of the pathophysiology of epilepsy, especially of forms characterized by the onset of seizures from a specific area of ​​the brain ( partial-onset epilepsy ). Although most patients respond to medication, approximately 20% -30% do not improve with or fail to tolerate antiepileptic drugs . [5] [6] For such patients, surgeryto remove the epileptogenic zone may be offered in a small minority, but it is not possible that the seizures arise from brain areas that are essential for language, vision, movement or other functions. As a result, many people with epilepsy are left without any treatment options, and thus there is a strong need for the development of innovative methods for treating epilepsy.

Throughout the use of viral vector gene transfer, RNA to the epileptogenic zone, several neuropeptides , ion channels and neurotransmitter receptors have shown potential as transgenes for epilepsy treatment. Among vectors are adenovirus and adeno-associated virus vectors (AAV), which have the properties of high and efficient transduction, ease of production in high volumes, wide range of hosts, and extended gene expression. [7] Lentiviral vectors have also been shown.

Clinical research

Amongst the challenges of clinical translation, the possibility of immune responses to viral vectors and transgenes and the possibility of insertional mutagenesis , which can be detrimental to patient safety. [8] Scaling up from the volume needed for animal trials is an area of ​​difficulty, but it has been overcome in other diseases. With its size of less than 20 nm, AAV in the context of these problems, allowing for its passage through the extracellular space, leading to widespread transfection. Although it may be important for the treatment of neuronal diseases, it is important that neuronal diseases be avoided and that they are less prone to insertional mutagenesis

Viral approaches in preclinical development

In a method for treating epilepsy, the pathophysiology of epilepsy is considered. As the seizures are typically characterized by excessive excitatory neurons, the logical goal for gene therapy is to reduce excitation or enhance inhibition. Out of the viral approaches, neuropeptide transgenes being researched are somatostatin, galanin, and neuropeptide Y (NPY). However, adenosine and gamma-aminobutryic acid (GABA) and GABA receptors are gaining more momentum as well. Other transgenes being studied are potassium channels and tools for on-demand suppression of excitability ( optogenetics and chemogenetics ).

Adenosine

Adenosine is an inhibitory nucleoside that doubles up as a neuromodulator , aiding in the modulation of brain function. It has anti-inflammatory properties, in addition to neuroprotective and anti-epileptic properties. [6] The most prevalent theory is that there is an increased expression of adenosine kinase (ADK). The increase in adenosine kinase results in an increased metabolic rate for adenosine nucleosides. Nucleic acid deficiency in the presence of anti-epileptic properties and the overexpression of ADK, seizures are triggered, resulting in the development of epileptogenesis . [7] Studies have shown that ADK overexpression results fromastrogliosis following a brain injury, which can lead to the development of epileptogenesis. While ADK overexpression leads to increased susceptibility to seizures, the effects can be counteracted and moderated by adenosine. [9] Based on adenosine in preventing seizures, in addition to its FDA approval in the treatment of other ailments such as tachycardia and chronic pain, adenosine is an ideal target for the development of anti-epileptic gene therapies. [10]

Galanin

Galanin , found primarily within the central nervous system (limbic system, piriform cortex, and amygdala), plays a role in the reduction of long-term potentiation (LTP), regulating consumption habits, and inhibiting seizure activity. [11]Introduced back in the 1990s by Mazarati et al., Galanin has been shown to have neuroprotective and inhibitory properties. Through the use of mice are deficient in GalR1 That receptors, a picrotoxin-kindled model Was Utilized to show That galanin plays a role in modulating and Preventing hilar cell loss as well as decreasing the duration of induced seizures. [12]Conducted studies confirming these findings of prevention, decreasing the incidence and duration of seizures, increasing the stimulation threshold required to induce seizures, and suppressing the release of glutamate that would increase susceptibility to seizure activity. [6] [11] [13] Galanin expression can be used to reduce and reduce seizure activity and limit seizure cell death. [11]

Neuropeptide Y

Neuropeptide Y (NPY), which is found in the autonomic nervous system , helps modulate the hypothalamus, and therefore, consumption habits. [6] Experiments have been conducted to determine the effect of NPY on animal models before and after induced seizures. [6] [14] To evaluate-the effect prior to seizures, one study vectors inserted 8 weeks prior to kindling , showing year Increase in seizure threshold. In order to evaluate the effects after epileptogenesiswere present, the vectors were injected into the hippocampus of rats after seizures were induced. This resulted in a reduction of seizure activity. These studies established that NPY increased the seizure threshold in rats, arrested disease progression, and reduced seizure duration. [6] [14] After examining the effects of NPY on behavioral and physiological responses, it was discovered that it had no effect on LTP, learning, or memory. [14] A protocol for NPY gene transfer is being reviewed by the FDA. [13]

Somatostatin

Somatostatin is a neuropeptide and neuromodulator that plays a role in the regulation of hormones and aids in sleep and motor activity. It is primarily found in interneurons that modulating the firing rates of pyramidal cells primarily at a local level. They feed-forward inhibit pyramidal cells. In a series of studies where somatostatin is expressed in a rodent kindling model , it was concluded that somatostatin resulted in a decreased average duration for seizures, increasing its potential as an anti-seizure drug. [15]The theory in utilizing somatostatin is that if pyramidal cells are eliminated, then the feed forward, otherwise known as inhibition, is lost. Somatostatin containing interneurons carry the neurotransmitter GABA, which primarily causes hyperpolarizes the cells, which is where the feed forward theory is derived from. The hope of gene therapy is that by overexpressing somatostatin in specific cells, and increasing the GABAergic tone, it is possible to restore balance between inhibition and excitation. [6] [14]

Potassium channels

Kv1.1 is a voltage-gated potassium channel encoded by the KCNA1 gene. It is published in the brain and peripherals, and plays a role in controlling the excitability of neurons and the amount of neurotransmitter released from axon terminals. Successful gene therapy using lentiviral delivery of KCNA1 has been reported in a rodent model of focal motor cortex epilepsy [16] The treatment was well tolerated, with no detectable effect on sensorimotor coordination.

Optogenetics

A potential obstacle to clinical gene therapy is that viral vector-mediated manipulation of the genetic make-up of neurons is irreversible. An alternative approach for the use of neuron and excitability. The first such approach has been used optogenetics . Several laboratories have shown that the inhibitory light-sensitive protein Halorhodopsin can suppress seizure-like discharges in vitro and in vivo epileptic activity. [17] [18] [19] [20] A draw-back of Optogenetics Is That Light needs to be Delivered to the area of the brain conjunctival phrase the opsin. This can be achieved with laser-coupled fiber-optics or light-emitting diodes, but these are invasive.

Chemogenetics

An alternative approach for on-demand control of excitability that does not require light delivery to the brain is to use chemogenetics . This report is based on a mutated receptor in the seizure focus, which does not respond to endogenous neurotransmitters but can be activated by an exogenous drug. G-protein-coupled receptors are mutated in this way by Designer Receptors Exclusively Activated by Drugs Designer (DREADDs) . Dreadd hM4D (Gi), which is derived from the M4 muscarinic receptor. [21]AAV-mediated expression of hM4D (Gi) in a rodent model of focal epilepsy on its own no effect, but when activated by the drug clozapine-N-oxide it suppressed seizures. The treatment has not been detectable side effects and is, in principle, suitable for clinical translation .

Non-viral approaches

Magnetofection is done through the use of super paramagnetic iron oxide nanoparticles coated with polyethylenimine . Iron oxide nanoparticles are ideal for biomedical applications in the body due to their biodegradable, cationic, non-toxic, and FDA-approved nature. Under the conditions of the invention, the receptors of interest are coated with nanoparticles. The receptors will then be in the home. Once the particle docks, the DNA is delivered to the cell via pinocytosis or endocytosis. On delivery, the temperature is slightly increased, the lysing the iron oxide nanoparticle and releasing the DNA. Overall, the technique is useful for fighting slow vector accumulation and low concentration at target areas. The technique is also customizable to the physical and biochemical properties of the receptors by modifying the characteristics of the iron oxide nanoparticles. [22] [23]

Future implications

The use of gene therapy in neurological disorders Treating epilepsy Such As has presented Itself as an increasingly viable area of Ongoing research with the primary targets being white somatostatin , galanin , neuropeptide y , potassium channels , Optogenetics and chemogenetics for epilepsy. The field of gene therapy continues to grow and show promising results for the treatment of epilepsy among other diseases, providing additional methods for delivery, and finding possible methods for scaling up delivery volumes. [24] [25]

References

  1. Jump up^ Walker, MC .; Schorge, S .; Kullmann, DM .; Wykes, RC .; Heeroma, JH .; Mantoan, L. (Sep 2013). “Gene therapy in status epilepticus”. Epilepsia . 54 Suppl 6: 43-5. doi : 10.1111 / epi.12275 . PMID  24001071 .
  2. Jump up^ Palfi, Stéphane; Gurruchaga, Jean Marc; Ralph, G. Scott; Lepetit, Helene; Lavisse, Sonia; Buttery, Philip C .; Watts, Colin; Miskin, James; Kelleher, Michelle (2014-03-29). “Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial”. Lancet . 383 (9923): 1138-1146. doi :10.1016 / S0140-6736 (13) 61939-X . ISSN  1474-547X . PMID  24412048 .
  3. Jump up^ Hirose, G (May 2013). “An Overview of epilepsy: its history, classification, pathophysiology, and management”. Brain Nerve . 65 (5): 509-20. PMID  23667116 .
  4. Jump up^ Sander, J .; Shorvon, S. (Nov 1996). “Epidemiology of the epilepsies” . J Neurol Neurosurg Psychiatry . 61 (5): 433-433. doi : 10.1136 / jnnp.61.5.433 . PMC  1074036  . PMID  8965090 .
  5. Jump up^ Pati, S .; Alexopoulos AV (Jul 2010). “Pharmoresistant epilepsy: from pathogenesis to current and emerging therapies”. Cleveland Clinic Journal of Medicine . 77 (7): 457-67. doi : 10.3949 / ccjm.77a.09061 . PMID  20601619 .
  6. ^ Jump up to:g Weinberg, Mark; McCown, Thomas (June 2013). “Current prospects and challenges for epilepsy gene therapy”. Experimental Neurology . 244 (Special): 27-35. doi : 10.1016 / j.expneurol.2011.10.003 .
  7. ^ Jump up to:b Naegele, Janice; Xu M; Yang J; Royston S; Ribeiro E (September 2009). “Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy” . Elsevier . 58 (6): 855-64. doi : 10.1016 / j.neuropharm.2010.01.019 . PMC  2838966  . PMID  20146928 .
  8. Jump up^ Giacca, Mauro (2010). Gene Therapy . New York: Springer. pp. 284-86. ISBN  978-88-470-1642-2 .
  9. Jump up^ Boison, Detlev (October 2006). “Adenosine kinase, epilepsy, and stroke: mechanisms and theory”. Elsevier . 27 (12): 652-8. doi : 10.1016 / j.tips.2006.10.008 . PMID  17056128 .
  10. Jump up^ Boison, Detlev; Stewart K (May 2009). “Therapeutic epilepsy research: from pharmacological rationale to focal adenosine augmentation” . Elsevier . 78 (12): 1428-37. doi : 10.1016 / j.bcp.2009.08.005 . PMC  2766433  . PMID  19682439 .
  11. ^ Jump up to:c McCown, Thomas (July 2006). “Adeno-Associated Virus Vector-Mediated Expression and Constitutive Secretion of Galanin Suppresses Limbic Seizure Activity”. The Journal of the American Society for Experimental NeuroTherapeutics . 14 (1): 63-8. doi : 10.1016 / j.ymthe.2006.04.004 . PMID  16730475 .
  12. Jump up^ Mazarati, AM; Halaszi E; Telegdy G (1992). “Anticonvulsive effects of galanin administered in the central nervous system on the picrotoxin-kindled seizure syndrome in rats”. Brain Research . 589 (1): 164-66. doi : 10.1016 / 0006-8993 (92) 91179-1 .
  13. ^ Jump up to:b Loscher, W; Gernert M; Heinemann U (February 2008). “Cell and gene therapies in epilepsy – promising avenues or blind alleys?”. Trends in Neurosciences . 31 (2): 62-73. doi : 10.1016 / j.tins.2007.11.012 . PMID  18201772 .
  14. ^ Jump up to:d Simonato Michelle (October 2013). “Gene therapy for epilepsy”. Epilepsy & Behavior . 38 : 125-130. doi : 10.1016 / j.yebeh.2013.09.013 . PMID  24100249 .
  15. Jump up^ Zafar, Rabia; King M; Carney P (July 2011). “Adeno associated viral vector-mediated expression of somatostatin in rat hippocampus suppresses seizure development”. Elsevier . 509 (2): 87-91. doi : 10.1016 / j.neulet.2011.12.035 . PMID  22245439 .
  16. Jump up^ Wykes, Robert C .; Heeroma, Joost H .; Mantoan, Laura; Zheng, Kaiyu; MacDonald, Douglas C .; Deisseroth, Karl; Hashemi, Kevan S .; Walker, Matthew C .; Schorge, Stephanie (2012-11-21). “Optogenetic and Potassium Channel Gene Therapy in a Rodent Model of Focal Neocortical Epilepsy” . Science Translational Medicine . 4 (161): 161ra152-161ra152. doi : 10.1126 / scitranslmed.3004190 . ISSN  1946-6234 . PMC  3605784  . PMID  23147003 .
  17. Jump up^ Tønnesen, Jan; Sørensen, Andreas T .; Deisseroth, Karl; Lundberg, Cecilia; Kokaia, Merab (2009-07-21). “Optogenetic control of epileptiform activity” . Proceedings of the National Academy of Sciences of the United States of America . 106 (29): 12162-12167. doi : 10.1073 / pnas.0901915106 . ISSN  1091-6490 . PMC  2715517  . PMID  19581573 .
  18. Jump up^ Wykes, Robert C .; Heeroma, Joost H .; Mantoan, Laura; Zheng, Kaiyu; MacDonald, Douglas C .; Deisseroth, Karl; Hashemi, Kevan S .; Walker, Matthew C .; Schorge, Stephanie (2012-11-21). “Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy” . Science Translational Medicine . 4 (161): 161,? 152. doi : 10.1126 / scitranslmed.3004190 . ISSN  1946-6242 . PMC  3605784  . PMID  23147003 .
  19. Jump up^ Krook-Magnuson, Esther; Armstrong, Caren; Oijala, Mikko; Soltesz, Ivan (2013-01-01). “On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy” . Nature Communications . 4 : 1376. doi : 10.1038 / ncomms2376 . ISSN  2041-1723 . PMC  3562457  . PMID  23340416 .
  20. Jump up^ Paz, Jeanne T .; Davidson, Thomas J .; Frechette, Eric S .; Delord, Bruno; Parada, Isabel; Peng, Kathy; Deisseroth, Karl; Huguenard, John R. (2013-01-01). “Closed-loop optogenetic control of thalamus as a tool for seizures after cortical injury” . Nature Neuroscience . 16 (1): 64-70. doi : 10.1038 / nn.3269 . ISSN  1546-1726 . PMC  3700812  . PMID  23143518 .
  21. Jump up^ Kätzel, Dennis; Nicholson, Elizabeth; Schorge, Stephanie; Walker, Matthew C .; Kullmann, Dimitri M. (2014-05-27). “Chemical-genetic attenuation of focal neocortical seizures” . Nature Communications . 5 : 3847. doi : 10.1038 / ncomms4847 . ISSN  2041-1723 . PMC  4050272  . PMID  24866701 .
  22. Jump up^ Arsianti, Maria; Lim M; Khatri A; Russell P; Amal R (2008). “Promise of Novel Magnetic Nanoparticles for Gene Therapy Application: Synthesis, Stabilization, and Gene Delivery”. Chemeca 2008: Towards a Sustainable Australasia : 734.
  23. Jump up^ Scherer, F; Anton M; Schillinger U; Henke J; Bergemann C; Kruger A; Gansbacher B; Plank C (January 2002). “Magnetofection: Magnetofection: Magnetofection: Magnetofection: Magnetofection. Gene Therapy . 9 (2): 102-9. doi : 10.1038 / sj.gt.3301624 . PMID  11857068 .
  24. Jump up^ Krook-Magnuson, Esther; Soltesz, Ivan (2015-03-01). “Beyond the hammer and the scalpel: selective circuit control for epilepsies” . Nature Neuroscience . 18 (3): 331-338. doi : 10.1038 / nn.3943 . ISSN  1546-1726 . PMC  4340083  . PMID  25710834 .
  25. Jump up^ Kullmann, Dimitri M .; Schorge, Stephanie; Walker, Matthew C .; Wykes, Robert C. (2014-05-01). “Gene therapy in epilepsy-is it time for clinical trials?”. Nature Reviews. Neurology . 10 (5): 300-304. doi : 10.1038 / nrneurol.2014.43 . ISSN  1759-4766 . PMID  24638133 .

Leave a Comment

Your email address will not be published. Required fields are marked *