Gene therapy for epilepsy

Generalized wave discharges in EEG

Gene therapy is being studied for some forms of epilepsy.[1] It aims to utilize viral and non-viral vectors in the delivery of DNA to target areas for the treatment of patients before their diseases progresses. Gene therapy has delivered promising results in animal trials and other pre-clinical settings, leading to being conducted in hopes of developing gene therapies for neurological disorders such as epilepsy.

Overview

Epilepsy is a chronic set of neurological disorders that are characterized by seizures, affecting over 50 million people, or 0.4% - 1% of the global population.[2][3] There is a basic understanding of the pathophysiology and its existing treatments, including medication, surgery, and dieting. While these treatments are effective for many, there are approximately 20% - 30% who do not improve with antiepileptic drugs.[4][5] As a result, many epileptics are left without any treatment options to consider, and thus there is a strong need for the development of innovative methods for treating epilepsy.

Through the use of viral vector gene transfer, with the purpose of delivering DNA to targets for treatment, multiple neuropeptides have shown potential as targets for epilepsy treatment. Among those are adenovirus and adeno-associated virus vectors (AAV), which have the properties of high and efficient transduction, ease of production in high volumes, a wide range of hosts, and extended gene expression.[6]

Clinical research

Attention has been brought to the need for extensive consideration of areas such as immunoresponses and insertional mutagenesis, which can be detrimental to patient safety.[7]

Another key challenge is delivering enough DNA volume to target areas with the least resistance and insertional mutagenesis. Scaling up from the volume needed for animal trials to that needed for effective human transfection is an area of difficulty. With its size of less than 20 nm, AAV in part addresses this problem, allowing for its passage through the extracellular space, leading to widespread transfection.

Other challenges in the use of gene therapy for treating human diseases that need to be addressed include: understanding how epilepsy fosters unfavorable conditions for grafts of neural precursors, developing an alternative vehicle for delivering drugs to target areas without requiring surgery, developing innovative drugs for epilepsy, deciding what DNA to transfect, and mutagenesis.[5][7]

Viral approaches

In finding a method for treating epilepsy, the pathophysiology of epilepsy is considered. As the seizures that characterize epilepsy are a result of excitatory signals, the logical goal for gene therapy treatment is to balance excitatory and inhibitory signals. Out of the viral approaches, the three main targets being researched are Somatostatin, Galanin, and Neuropetide Y (NPY). However, Adenosine and gamma-aminobutryic acid (GABA) and GABA Receptors are gaining more momentum as well.

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.[5] The most prevalent theory is that upon brain injury there is an increased expression of the adenosine kinase (ADK). The increase in adenosine kinase results in an increased metabolic rate for adenosine nucleosides. Due to the decrease in these nucleosides that possess anti-epileptic properties and the overexpression of the ADK, seizures are triggered, potentially resulting in the development of epileptogenesis.[6] Studies have shown that ADK overexpression results from astrogliosis 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.[8] Based on the properties afforded by 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.[9]

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, as well as inhibiting seizure activity.[10] Introduced back in the 1990s by Mazarati et al., galanin has been shown to have neuroprotective and inhibitory properties. Through the use of mice that are deficient in GalR1 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.[11] Conducted studies confirm these findings of preventing hilar hair cell loss, decreasing the number and duration of induced seizures, increasing the stimulation threshold required to induce seizures, and suppressing the release of glutamate that would increase susceptibility to seizure activity.[5][10][12] Galanin expression can be utilized to significantly moderate and reduce seizure activity and limit seizure cell death.[10]

Neuropeptide Y

Neuropeptide Y (NPY), which is found in the autonomic nervous system, helps modulate the hypothalamus, and therefore, consumption habits.[5] Experiments have been conducted to determine the effect of NPY on animal models before and after induced seizures.[5][13] To evaluate the effect prior to seizures, one study inserted vectors 8 weeks prior to kindling, showing an increase in seizure threshold. In order to evaluate the effects after epileptogenesis was 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.[5][13] After examining the effects of NPY on behavioral and physiological responses, it was discovered that it had no effect on LTP, learning, or memory.[13] A protocol for NPY gene transfer is being reviewed by the FDA.[12]

Somatostatin

Somatostatin is a neuropeptide and neuromodulator that plays a role in the regulation of hormones as well as aids in sleep and motor activity. It is primarily found in interneurons that modulates the firing rates of pyramidal cells primarily at a local level. They feed-forward inhibit pyramidal cells. In a series of studies where somatostatin was 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.[14] 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 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.[5][13]

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 gene transfer conditions, the receptors of interest are coated with the nanoparticles. The receptors will then home in and travel to the target of interest. Once the particle docks, the DNA is delivered to the cell via pinocytosis or endocytosis. Upon delivery, the temperature is increased ever so slightly, lysing the iron oxide nanoparticle and releasing the DNA. Overall, the technique is useful for combatting slow vector accumulation and low vector 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.[15][16]

Future implications

The use of gene therapy in treating neurological disorders such as epilepsy has presented itself as an increasingly viable area of ongoing research with the primary targets being somatostatin, galanin, and neuropeptide y for epilepsy. As the field of gene therapy continues to grow and show promising results for the treatment of epilepsy among other diseases, additional research needs to be done in ensuring patient safety, developing alternative methods for DNA delivery, and finding feasible methods for scaling up delivery volumes. In addition, more quantitative methods of measuring the effectiveness of potential therapies to be considered include, but are not limited to, the method of kindling, duration of the latent period, and seizure frequency.[17]

References

  1. ↑ 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. ↑ Hirose, G (May 2013). "An Overview of epilepsy: its history, classification, pathophysiology, and management". Brain Nerve 65 (5): 509–20. PMID 23667116.
  3. ↑ 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. PMID 8965090.
  4. ↑ 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.
  5. 1 2 3 4 5 6 7 8 Weinberg, Marc; 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.
  6. 1 2 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. PMID 20146928.
  7. 1 2 Giacca, Mauro (2010). Gene Therapy. New York: Springer. pp. 284–86. ISBN 978-88-470-1642-2.
  8. ↑ 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.
  9. ↑ 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. PMID 19682439.
  10. 1 2 3 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.
  11. ↑ Mazarati, A.M.; Halaszi E; Telegdy G (1992). "Anticonvulsive effects of galanin administered into the central nervous system upon the picrotoxin-kindled seizure syndrome in rats". Brain Research 589 (1): 164–66. doi:10.1016/0006-8993(92)91179-i.
  12. 1 2 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.
  13. 1 2 3 4 Simonato, Michelle (October 2013). "Gene therapy for epilepsy". Epilepsy & Behavior 38: 125–130. doi:10.1016/j.yebeh.2013.09.013. PMID 24100249.
  14. ↑ 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.
  15. ↑ Arsianti, Maria; Lim M; Khatri A; Russell P; Amal R (2008). "Promise of Novel Magnetic Nanoparticles for Gene Therapy Application: Synthesis, Stabilisation, and Gene Delivery". Chemeca 2008: Towards a Sustainable Australasia: 734.
  16. ↑ Scherer, F; Anton M; Schillinger U; Henke J; Bergemann C; Kruger A; Gansbacher B; Plank C (January 2002). "Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo". Gene Therapy 9 (2): 102–9. doi:10.1038/sj.gt.3301624. PMID 11857068.
  17. ↑ Dudek, Edward F. (April 2009). "Commentary: A Skeptical View of Experimental Gene Therapy to Block Epileptogenesis". Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics 6 (2): 319–22. doi:10.1016/j.nurt.2009.01.020. PMID 19332326.
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