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A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease

Nature Medicine volume 11, pages 551–555 (2005)Cite this article

Abstract

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

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Figure 1: Cognitive outcome, MMSE.
Figure 2: Cognitive outcome, ADAS-Cog.
Figure 3: PET scans.
Figure 4: Trophic response to NGF in the human brain.

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Acknowledgements

We acknowledge the pioneering work of F. Gage in laying the foundation for this clinical program. We thank B. Hempstead for providing proNGF and antibody, T. Mead for performing immunoelectrophoresis and R. Bartus for helpful advice. Supported by the Shiley Family Foundation and the Institute for the Study of Aging.

Author information

Authors and Affiliations

  1. Department of Neurosciences, University of California at San Diego, La Jolla, 92093, California, USA

    Mark H Tuszynski, Leon Thal, Mary Pay, David P Salmon, Armin Blesch, H Lee Vahlsing, Gilbert Ho, Gang Tong, Lawrence Hansen & James Conner

  2. Veterans Affairs Medical Center, San Diego, 92161, California, USA

    Mark H Tuszynski, Leon Thal & H Lee Vahlsing

  3. Department of Surgery, University of California at San Diego, La Jolla, 92093, California, USA

    Hoi Sang U

  4. Department of Surgery, Rush University Medical Center, Chicago, 60612, Illinois, USA

    Roy Bakay

  5. Department of Anesthesiology, University of California at San Diego, La Jolla, 92093, California, USA

    Piyush Patel

  6. Department of Neurology, University of California – Irvine, Irvine, 92697, California, USA

    Steven G Potkin

  7. Departments of Anatomy and Neurobiology, University of California – Irvine, Irvine, 92697, California, USA

    James Fallon & Christine Gall

  8. Department of Neurosciences, Rush University Medical Center, Chicago, 60612, Illinois, USA

    Elliott J Mufson & Jeffrey H Kordower

Authors
  1. Mark H Tuszynski
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  17. Christine Gall
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  18. James Conner
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Corresponding author

Correspondence to Mark H Tuszynski.

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Competing interests

Mark H. Tuszynski, Armin Blesch and Jeffrey H. Kordower are scientific founders of Ceregene, Inc. None of these individuals participated in subject selection, or in assessment of safety and efficacy.

Supplementary information

Supplementary Fig. 1

Using immunoelectrophoresis and comparison to known quantities of loaded proNGF and NGF, the ratio of proNGF:NGF was less than 1:100. (PDF 37 kb)

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Tuszynski, M., Thal, L., Pay, M. et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11, 551–555 (2005). https://doi.org/10.1038/nm1239

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