Gene therapy in the adult primate brain: Intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration

M. H. Tuszynski, Jeffrey A Roberts, M. C. Senut, H. S. U, F. H. Gage

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

Gene therapy may be a useful means of delivering substances to the brain that are capable of preventing neuronal degeneration. In the present experiment, we determined whether intraparenchymal transplants of primary autologous cells genetically modified to produce nerve growth factor (NGF) would prevent injury-induced degeneration of cholinergic neurons. Cultured primary monkey fibroblasts were genetically modified to produce human NGF, and secreted 13.2 ng NGF/106 cells/h in vitro. Adult monkeys then underwent fornix transections to induce degeneration of basal forebrain cholinergic neurons, and received autologous grafts of either NGF-producing or control, β-galactosidase-producing fibroblasts directly into the basal forebrain region. One month later, 61.7±8.9% of cholinergic neurons remained indentiffable in NGF-graft recipients compared to 26.2±5.0% in control graft recipients (P < 0.02). Neuronal protection correlated with the accuracy of graft placement: up to 92% protection from neuronal degeneration occurred when NGF-secreting grafts were accurately placed immediately adjacent to injured neurons. Thus, intraparenchymal NGF delivery to the adult primate brain by gene transfer can prevent the degeneration of basal forebrain cholinergic neurons. Gene therapy can target intraparenchymal brain sites for regionally specific neurotrophin delivery, thereby avoiding limitations imposed by diffusion of substances across the blood-brain barrier and through CNS parenchyma, while avoiding adverse effects of neurotrophic factors delivered in a non-directed manner to the central nervous system. The delivery of NGF by gene transfer to the brain merits further study as a means of preventing cholinergic neuronal degeneration in human disorders such as Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)305-314
Number of pages10
JournalGene Therapy
Volume3
Issue number4
StatePublished - Apr 1996

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Keywords

  • Alzheimer's disease
  • Cholinergic neurons
  • Gene therapy
  • Hippocampus
  • Medial septum
  • Nerve growth factor

ASJC Scopus subject areas

  • Genetics

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