Contemporary antiepileptic drugs are ineffective in approximately 30% of the patients. These patients continue to experience seizures and, in many cases, their seizures increase in frequency and become associated with significant cognitive decline and psychiatric disorders (Klein et al., 2018). The delivery of trophic factors such as glial cell-derived neurotrophic factor (GDNF) to the CNS has tremendous potential for treating a range of diseases including epilepsy. We have developed a clinically-validated, implantable cell encapsulation system (EC) that delivers high levels of GDNF in a selective, long-term and stable manner to the epileptogenic area. As such, this therapeutic technology platform combines the potency of de novo in situ synthesis of cell-derived GDNF with the safety of an implantable, biocompatible, and retrievable medical device. This approach is based on enclosing ARPE-19 cells genetically modified to secrete GDNF in an immunoprotective membrane before transplantation (Fjord-Larsen et al., 2012; Emerich et al., 2014). Initial studies confirmed the long-term (24 weeks) and targeted delivery of GDNF to the rat hippocampus. In subsequent studies, pilocarpine-treated rats, while experiencing spontaneous recurring seizures, received bilateral implants of EC-GDNF devices into the ventral hippocampus. While the number of seizures continued unimpeded in control rats, treatment with EC-GDNF devices reduced seizures by approximately 80% within 2 weeks and by more than 90% within 3 months. These effects persisted even after device retrieval, suggesting potential disease-modifying benefits. Because neuropsychological impairment is a critical co-morbidity of chronic epilepsy we investigated the effects of EC-GDNF on the nature and time course of anxiety-like behaviours and cognitive impairments occurring in pilocarpine treated rats. Importantly, treatment with EC-GDNF maintained normal learning and memory capabilities and normal anxiety-like behaviour. These neurological benefits were associated with the normalization of several anatomical alterations accompanying chronic epilepsy, including preventing hippocampal atrophy, cell degeneration, loss of parvalbumin positive interneurons, and abnormal neurogenesis (Paolone et al., under revision). These studies consistently demonstrated that encapsulated GDNF-secreting cells produce long-term and robust elevations in hippocampal GDNF that are well-tolerated, efficacious and perhaps disease modifying across a spectrum of epilepsy-relevant neurological measures. This approach represents a potentially novel and effective treatment for epilepsy.
Encapsulated cell therapy in a rat model of epilepsy: long-term, stable, and efficacious targeting of the hippocampus with GDNF
Giovanna Paolone
Conceptualization
;
2018-01-01
Abstract
Contemporary antiepileptic drugs are ineffective in approximately 30% of the patients. These patients continue to experience seizures and, in many cases, their seizures increase in frequency and become associated with significant cognitive decline and psychiatric disorders (Klein et al., 2018). The delivery of trophic factors such as glial cell-derived neurotrophic factor (GDNF) to the CNS has tremendous potential for treating a range of diseases including epilepsy. We have developed a clinically-validated, implantable cell encapsulation system (EC) that delivers high levels of GDNF in a selective, long-term and stable manner to the epileptogenic area. As such, this therapeutic technology platform combines the potency of de novo in situ synthesis of cell-derived GDNF with the safety of an implantable, biocompatible, and retrievable medical device. This approach is based on enclosing ARPE-19 cells genetically modified to secrete GDNF in an immunoprotective membrane before transplantation (Fjord-Larsen et al., 2012; Emerich et al., 2014). Initial studies confirmed the long-term (24 weeks) and targeted delivery of GDNF to the rat hippocampus. In subsequent studies, pilocarpine-treated rats, while experiencing spontaneous recurring seizures, received bilateral implants of EC-GDNF devices into the ventral hippocampus. While the number of seizures continued unimpeded in control rats, treatment with EC-GDNF devices reduced seizures by approximately 80% within 2 weeks and by more than 90% within 3 months. These effects persisted even after device retrieval, suggesting potential disease-modifying benefits. Because neuropsychological impairment is a critical co-morbidity of chronic epilepsy we investigated the effects of EC-GDNF on the nature and time course of anxiety-like behaviours and cognitive impairments occurring in pilocarpine treated rats. Importantly, treatment with EC-GDNF maintained normal learning and memory capabilities and normal anxiety-like behaviour. These neurological benefits were associated with the normalization of several anatomical alterations accompanying chronic epilepsy, including preventing hippocampal atrophy, cell degeneration, loss of parvalbumin positive interneurons, and abnormal neurogenesis (Paolone et al., under revision). These studies consistently demonstrated that encapsulated GDNF-secreting cells produce long-term and robust elevations in hippocampal GDNF that are well-tolerated, efficacious and perhaps disease modifying across a spectrum of epilepsy-relevant neurological measures. This approach represents a potentially novel and effective treatment for epilepsy.File | Dimensione | Formato | |
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