Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer

• Published in: Gene therapy Vol. 19; no. 10; pp. 1010 - 1017
• Main Authors: Fjord-Larsen, L, Kusk, P, Emerich, D F, Thanos, C, Torp, M, Bintz, B, Tornøe, J, Johnsen, A H, Wahlberg, L U
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2012; Nature Publishing Group
• Subjects: 631/378/1686; 631/61/51/201; 692/308/2778; 692/699/375/365/1283; Alzheimer Disease - therapy; Alzheimer's disease; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal experimentation; Animals; Applied cell therapy and gene therapy; Basal forebrain; Biological activity; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Brain; Brain - metabolism; Brain - pathology; Capsules; Care and treatment; Cell Biology; Cell Line, Transformed; Cognitive ability; DNA Transposable Elements; Drug delivery systems; Female; Forebrain; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Gene transfer; Genetic aspects; Genetic transformation; Genic rearrangement. Recombination. Transposable element; Growth factors; Health aspects; Health. Pharmaceutical industry; Human Genetics; Humans; Industrial applications and implications. Economical aspects; Medical sciences; Molecular and cellular biology; Molecular genetics; Nanotechnology; Neostriatum; Nerve Degeneration - chemically induced; Nerve Degeneration - genetics; Nerve Degeneration - therapy; Nerve growth factor; Nerve Growth Factor - genetics; Nerve Growth Factor - metabolism; Neurodegeneration; Neurodegenerative diseases; original-article; Physiological aspects; Proteins; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Rodents; Transfection; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transposons; cholinergic neurons; encapsulated cell biodelivery; preclinical validation; sleeping beauty transposon; NGF; rat QA model; Validation; Rat; Transposon; Rodentia; Central nervous system; Nerve growth factor; Encephalon; Genetic transfer; Vertebrata; Mammalia; Neuron; Microencapsulation; Models; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.178

Nerve growth factor (NGF) is a potential therapeutic agent for Alzheimer's disease (AD) as it has positive effects on the basal forebrain cholinergic neurons whose degeneration correlates with the cognitive decline in AD. We have previously described an encapsulated cell biodelivery device, NsG0202, capable of local delivery of NGF by a genetically modified human cell line, NGC-0295. The NsG0202 devices have shown promising safety and therapeutic results in a small phase 1b clinical study. However, results also show that the NGF dose could advantageously be increased. We have used the sleeping beauty transposon expression technology to establish a new clinical grade cell line, NGC0211, with at least 10 times higher NGF production than that of NGC-0295. To test whether encapsulation of this cell line provides a relevant dose escalation step in delivering NGF for treatment of the cognitive decline in AD patients, we have validated the bioactivity of devices with NGC0211 and NGC-0295 cells in normal rat striatum as well as in the quinolinic acid striatal lesion model. These preclinical animal studies show that implantation of devices with NGC0211 cells lead to significantly higher NGF output, which in both cases correlate with highly improved potency.