TABLE 1.
Gene and cell therapy for epilepsy.
| Therapeutic agent | Model | Dose and duration | Therapy results | References |
| GENE THERAPY | ||||
| LV encoding potassium channel Kv1.1 | Rat model of tetanus toxin- induced epilepsy | Single injection of 1–1.5 mL of LV [2.6 × 109 viral genomes (vg/mL)] into layer 5 of the right motor cortex | Decrease in the frequency of seizures over several weeks | Wykes et al., 2012 |
| AAV encoding potassium channel Kv1.1 | Rat model of kainic acid-induced status epilepticus | Single injection of 8.0 μl of AAV (8.3 × 1014 vg/mL) into dorsal and ventral hippocampus | Decrease in the frequency and duration of seizures | Snowball et al., 2019 |
| AAV9 encoding small guide RNAs for Kv1.1 upregulation | Mouse model of kainic acid-induced status epilepticus | Single injection of 300 nL of AAV9 (8 × 1012 vg/ml) into right ventral hippocampus | Decrease in the frequency of spontaneous generalized seizures | Colasante et al., 2020 |
| AAV1/2 encoding NPY | Rat model of kainate-induced seizures | Single injection of 2 μl of AAV2 (1012 vg/mL) into dorsal hippocampus | Decrease in the frequency of kainate-induced seizures | Gotzsche et al., 2012 |
| AAV encoding NPY | Rat model of kainate-induced seizures | Single injection of 10 μL of AAV (5 × 1011 vg/mL) into the right lateral ventricle | Decrease in the frequency of kainate-induced seizures | Dong et al., 2013; Zhang et al., 2013 |
| AAV1/2 encoding NPY and Y2 | Rat model of kainate-induced seizures | Single injection of 1 μl of AAV-NPY (1012 vg/mL) and 1.5 μl of AAV-Y2 (1012 vg/mL) into dorsal and ventral hippocampus | Decrease in the frequency of kainate-induced seizures | Ledri et al., 2016 |
| AAV1/2 encoding NPY | Rat model of genetic generalized epilepsy | Single injection of 3 μl of AAV (6.6 × 1012 vg/ml) into thalamus and 1 μl into SC | Decrease in the frequency and duration of seizures in the thalamus, decrease in the frequency of seizures in the SC | Powell et al., 2018 |
| AAV1 encoding NPY and Y2 | Rat model of kainate-induced seizures | Single injection of 3 μL of AAV (1012 vg/mL) into hippocampus | Decrease in the frequency of seizures | Melin et al., 2019 |
| AAV2 encoding GDNF | Rat model of kindling-induced epilepsy | Single injection of 1 and 2 μl of virus (2.1 × 1012 vg/mL) into dorsal and ventral hippocampus | Decrease in the frequency of seizures, increase in seizure induction threshold | Kanter-Schlifke et al., 2007 |
| AAV9 encoding miR-ADK | Rat model of kainate-induced seizures | Single injection of 3 μL of AAV (9.48 × 1011 vg/mL) vector infused into hippocampus | Decrease in the frequency of seizures, protection of dentate hilar neurons | Young et al., 2014 |
| AAV5 encoding preprosomatostatin | Rat model of kindling-induced epilepsy | Single injection of 2 μL of AAV (4.19 × 1013 vg/mL) into the left and right CA1 region and dentate gyrus | Development of seizure resistance in 50% of animals | Natarajan et al., 2017 |
| AAV8 encoding GAD67 | The EL/Suz mouse model of epilepsy | Single injection of 3 μL of AAV (1 × 1010 vg/mL) bilaterally into the CA3 region of hippocampus | Significant reduction in seizure generation | Shimazaki et al., 2019 |
| AAV2 encoding galanin | Rat model of kainate-induced seizures | Single injection of 2 μl of AAV (8 × 1012 vg/mL) into the piriform cortex | Prevention of kainic acid-induced seizures | McCown, 2006 |
| CELL THERAPY | ||||
| Nervous system cells | ||||
| Intravenous infusion of neurospheres | Rat model of pilocarpine-induced status epilepticus | Single intravenous injection of 2 × 106 cells | Decrease in the oxidative stress damage | de Gois da Silva et al., 2018 |
| Transplantation of medial ganglionic eminence-derived neural stem cell grafts | Rat model of kainic acid-induced status epilepticus | Single transplantation of 4 grafts of 80,000 cells in each side of the hippocampus (640,000 cells/rat) | Suppression of spontaneous recurrent motor seizures, an increase in the number of GABAergic neurons, restoration of GDNF expression. No improvement in cognitive function | Waldau et al., 2010 |
| GABAergic interneuron precursors from the medial ganglionic eminence | Kv1.1 mutant mice | Bilateral transplantation into the deep layers of the cortex at two different sites on the hemisphere (4 × 105 cells/mouse) | Decrease in the duration and frequency of spontaneous electrographic seizures | Baraban et al., 2009 |
| Human iPSCs-derived medial ganglionic eminence cells | Mouse model of pilocarpine-induced status epilepticus | Transplantation of cells in the hippocampus (3 × 105 cells/mouse) | Suppression of seizures, aggressiveness, hyperactivity, improvement of cognitive function | Cunningham et al., 2014 |
| Human iPSCs-derived medial ganglionic eminence cells | Rat model of kainic acid-induced status epilepticus | Single transplantation of 3 grafts of 100,000 cells in each side of the hippocampus (600,000 cells/rat) | Relief of spontaneous recurrent seizures, improvement of cognitive function and memory, reduction in the loss of interneurons | Upadhya et al., 2019 |
| MSCs | ||||
| Undifferentiated autologous bone marrow-derived MSCs (in combination with anti-epileptic drugs) | Patients with epilepsy | Single intravenous injection of 1–1.5 × 106 cells/kg and single intrathecal injection of 1 × 105 cells/kg after 5–7 days | No serious side effects. Reduction in frequency or complete stop of seizures, improvement of clinical manifestations | Hlebokazov et al., 2017; Hlebokazov et al., 2021 NCT02497443 |
| Adipose derived regenerative cells | Patients with autoimmune refractory epilepsy | Intrathecal injection of 4 ml of stromal fraction, 3 times every 3 months | Complete remission in 1 of 6 patients (within 3 years), mild and short-term reduction in seizure (3 of 6 patients). Improvement in patients’ daily functioning. No further regression was observed for 3 years | Szczepanik et al., 2020 NCT03676569 |
| Bone marrow-derived CD271+ MSCs and bone marrow MSCs | Pediatric patients with drug-resistant epilepsy | Combination therapy consisting of single intrathecal (0.5 × 109) and intravenous (0.38 × 109–1.72 × 109) injections of bone marrow-derived CD271+ MSC and four intrathecal injections of bone marrow MSC (18.5 × 106–40 × 106) every 3 months | Neurological and cognitive improvement, decrease in the frequency of seizures | Milczarek et al., 2018 |
| Bone marrow-derived MSCs | Rat model of pilocarpine- induced status epilepticus | Single intravenous injection of 3 × 106 cells/rat | Decrease in the frequency of seizures, increase in the number of neurons | Abdanipour et al., 2011 |
| Bone marrow-derived MSCs | Rat model of lithium-pilocarpine- induced epilepsy | Single intravenous injection of 106 cells/rat | Inhibition of epileptogenesis and improvement of cognitive functions | Fukumura et al., 2018 |
| Bone marrow-derived MSCs | Rat model of pilocarpine-induced status epilepticus | Single injection of 100,000 cells in each side of the hippocampus (200,000 cells/rat) or single intravenous injection of 3 × 106 cells/rat | Reduction of oxidative stress in the hippocampus, decrease in the levels of inflammatory cytokines (TNF-α and IL-1β) and an apoptotic marker (caspase 3). Improvement of neurochemical and pathological changes in the brain | Salem et al., 2018 |
| Neural-induced adipose-derived stem cells | Rat model of kainic acid-induced status epilepticus | Single transplantation into the hippocampus (50,000 cells/rat) | Decrease in seizure activity, recovery of memory and learning ability | Wang et al., 2021 |
| Umbilical cord blood MSCs | Rat model of pentylenetetrazole-induced chronic epilepsy | Single intravenous injection (106 cells/rat) | Decrease in the severity of seizures and oxidative stress damage, improved motor coordination and cognitive function | Mohammed et al., 2014 |
| Umbilical cord blood MSCs | Rat model of lithium-pilocarpine induced status epilepticus | Single transplantation into the hippocampus (5 × 105 cells/rat) | Partial restoration of glucose metabolism in the hippocampus, seizure frequency did not differ from the control group | Park et al., 2015 |
| Exosomes | ||||
| MSC-derived exosomes | Mouse model of pilocarpine-induced status epilepticus | Single intraventricular injection (30 μg) | Reduction in the intensity of manifestation of reactive astrogliosis and inflammatory response, improvement in cognitive functions and memory | Xian et al., 2019 |
| MSC-derived A1-exosomes | Mouse model of pilocarpine-induced status epilepticus | Two intranasal administrations after 18 h (15 μg) | Reduction in the loss of glutamatergic and GABAergic neurons, reduction in the inflammation, support of normal hippocampal neurogenesis, cognitive function, and memory | Long et al., 2017 |
| Mononuclear cells | ||||
| Bone marrow mononuclear cells | Patients with temporal lobe epilepsy | Single intra-arterial injection (1.52–10 × 108 cells/patient) | Decrease in the number of seizures, increase in average memory indicators. Complete disappearance of seizures in 40% of patients | DaCosta et al., 2018 NCT00916266 |
| Bone marrow mononuclear cells | Rat model of lithium-pilocarpine induced status epilepticus | Single intravenous injection (1 × 106 cells/rat) | Prevention of spontaneous recurrent seizures in the early stage of epilepsy, a significant reduction in the frequency and duration of seizures in the chronic phase | Costa-Ferro et al., 2010 |
| Bone marrow mononuclear cells | Mouse model of pilocarpine- induced status epilepticus | Single intravenous injection (2 × 106 cells/mouse) | Neuroprotective and anti-inflammatory effects, decrease in the loss of hippocampal neurons | Leal et al., 2014 |
| Encapsulated cell biodelivery | ||||
| Semipermeable capsule containing GDNF-secreting ARPE-19 cells (arising retinal pigment epithelia cells) | Rat model of pilocarpine- induced status epilepticus | Transplantation in the hippocampus (5 × 104 cells/capsule). GDNF concentration up to 566.79 ± 192.47 ng/24 h | Decrease in the frequency of seizures, cognitive function improvement, neuroprotective effect | Paolone et al., 2019 |
| Semipermeable capsule containing GDNF-secreting cells | Rat model of kindling-induced epilepsy | Transplantation in the hippocampus. High GDNF concentration –150.92 ± 44.51 ng/ml/24 h, low concentration – 0.04 ± 0.88 ng/ml/24 h | Low GDNF levels have an antiepileptic effect compared to elevated levels | Kanter-Schlifke et al., 2009 |
| Semipermeable capsule containing galanin-secreting ARPE-19 cells | Rat model of kindling-induced epilepsy | Transplantation in the hippocampus (6 × 104 cells/capsule) High galanin concentration – 12.6 ng/ml/24 h, low concentration – 8.3 ng/ml/24 h | High doses decrease the duration of focal seizures | Nikitidou et al., 2014 |
| Semipermeable capsule containing BDNF-secreting ARPE-19 cells | Rat model of pilocarpine- induced status epilepticus | Transplantation in the hippocampus (5 × 104 cells/capsule). BDNF concentration – 200–400 ng/24 h | Decrease in the frequency of seizures. Cognitive function improvement | Falcicchia et al., 2018 |
| Semipermeable capsule containing BDNF-secreting baby hamster kidney cells | Rat model of pilocarpine- induced status epilepticus | Transplantation in the hippocampus (106 cells/capsule) BDNF concentration – 7.2 ± 1.2 ng/24 h | Injection of low doses had a neuroprotective effect and stimulated neurogenesis | Kuramoto et al., 2011 |