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

Gene Therapy volume 19, pages 1010–1017 (2012)Cite this article

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Abstract

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.

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Acknowledgements

We wish to thank Dr Zsuzsanna Izsvák and Dr Zoltán Ivics for introducing us to the sleeping beauty transposon system as well as the generous assistance with NGF copy number determination. We thank Helle Nymark, Janni Larsen, Juliano Olsen, Marianne Kureer, Pia Knudsen, Hanne Fosmark and Helle T Wassmann for excellent technical assistance with cells and devices. Also, the technical assistance by Allan Kastrup with NGF purification and mass spectrometry analysis is highly appreciated.

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Authors and Affiliations

  1. NsGene A/S, Ballerup, Denmark

    L Fjord-Larsen, P Kusk, M Torp & J Tornøe

  2. NsGene Inc., Providence, RI, USA

    D F Emerich & L U Wahlberg

  3. CytoSolv Inc., Providence, RI, USA

    C Thanos & B Bintz

  4. Department of Clinical Biochemistry, Copenhagen, Denmark

    A H Johnsen

Authors
  1. L Fjord-Larsen
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  2. P Kusk
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Correspondence to L Fjord-Larsen.

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Competing interests

LF-L, PK, JT, MT and LUW are employed by NsGene A/S. This study was funded by NsGene A/S.

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Fjord-Larsen, L., Kusk, P., Emerich, D. et al. Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer. Gene Ther 19, 1010–1017 (2012). https://doi.org/10.1038/gt.2011.178

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