| Long-term, targeted delivery of GDNF from encapsulated cells is neuroprotective and reduces seizures in the pilocarpine model of epilepsy.
Paolone G1,2, Falcicchia C3,2, Lovisari F3, Kokaia M4, Bell WJ2, Fradet T2, Barbieri M3, Wahlberg LU2, Emerich DF2, Simonato M3,5,6.
Author information
1Department of Medical Science, Section of Pharmacology, Neuroscience Center, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy [email protected] Therapeutic, Inc. (formerly NsGene Inc.), Providence, RI, USA.3Department of Medical Science, Section of Pharmacology, Neuroscience Center, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.4Epilepsy Centre, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden.5Laboratory of Technologies for Advanced Therapy (LTTA), Technopole of Ferrara, Ferrara, Italy.6School of Medicine, University Vita-Salute San Raffaele, Milan, Italy.
Abstract
Neurotrophic factors are candidates for treating epilepsy but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin positive interneurons, and abnormal neurogenesis. These effects were associated with activation of GDNF receptors. All in all, these results support the concept that implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing pre-clinical evaluation and eventual clinical translation of this approach for epilepsy.SIGNIFICANCE STATEMENTEpilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically-validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (>90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.
www.ncbi.nlm.nih.gov/pubmed/30665947Journal of Neuroscience 21 January 2019
Long-term, targeted delivery of GDNF from encapsulated cells is neuroprotective and reduces seizures in the pilocarpine model of epilepsy
Giovanna Paolone, Chiara Falcicchia, Francesca Lovisari, Merab Kokaia, William J. Bell, Tracie Fradet, Mario Barbieri, Lars U. Wahlberg, Dwaine F. Emerich, and Michele Simonato
Journal of Neuroscience 21 January 2019, 0435-18; DOI: https://doi.org/10.1523/JNEUROSCI.0435-18.2018
Abstract
Neurotrophic factors are candidates for treating epilepsy but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin positive interneurons, and abnormal neurogenesis. These effects were associated with activation of GDNF receptors. All in all, these results support the concept that implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing pre-clinical evaluation and eventual clinical translation of this approach for epilepsy.
SIGNIFICANCE STATEMENT
Epilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically-validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (>90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.
www.jneurosci.org/content/early/201...CI.0435-18.2018
Author Information
Giovanna Paolone1,3,
Chiara Falcicchia1,3,
Francesca Lovisari1,
Merab Kokaia2,
William J. Bell3,
Tracie Fradet3,
Mario Barbieri1,
Lars U. Wahlberg3,
Dwaine F. Emerich3, and
Michele Simonato1,4,5
1Department of Medical Science, Section of Pharmacology, Neuroscience Center, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy
2Epilepsy Centre, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden
3Gloriana Therapeutic, Inc. (formerly NsGene Inc.), Providence, RI, USA
4Laboratory of Technologies for Advanced Therapy (LTTA), Technopole of Ferrara, Ferrara, Italy
5School of Medicine, University Vita-Salute San Raffaele, Milan, Italy
Correspondence: Giovanna Paolone, PhD, Current address: Department of Diagnostics and Public Health, Section of Pharmacology, University of Verona, P.le LA Scuro 10, 37134, Verona, Italy, Tel: (+39) 045 8027224, E-mail: [email protected]
www.jneurosci.org/content/early/201...ab-article-info
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