Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease
Open accessAbstract
IMPORTANCE: Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. OBJECTIVE: To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS: Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. MAIN OUTCOMES AND MEASURES: Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. RESULTS: Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE: These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Growth factor therapy induced sprouting by NGF, which persisted for 10 years after gene transfer and appeared safe.
“Growth factor therapy induced sprouting by NGF, which persisted for 10 years after gene transfer and appeared safe.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [101]
Tuszynski et al. (2015) subjected ten patients with early AD to NGF gene ex vivo or in vivo therapy.
“In an effort to test the ability to degenerate neurons in AD towards a nervous system growth factor (NGF), Tuszynski et al. (2015) subjected ten patients with early AD with NGF gene ex vivo or in vivo therapy [101].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [101]
The findings indicated positive response of neurons showing cell hypertrophy, axonal sprouting, and activation of functional markers.
“The findings indicated positive response of neurons showing cell hypertrophy, axonal sprouting, and activation of functional markers.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Neurotrophin signal transduction in the nervous system
Kaplan, D. R., & Miller, F. D. (2000) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00092-1 · Cited by 1,944 · see citing works
Jeurgen, K., Assheuer, J., & Paxinos, G. (1997) · Medical Entomology and Zoology · Cited by 1,416 · see citing works
A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease
Tuszynski, M. H., Thal, L., Pay, M., Salmon, D. P., U, H. S., Bakay, R., Patel, P., Blesch, A., Vahlsing, H. L., Ho, G., et al. (2005) · Nature Medicine · doi:10.1038/nm1239 · Cited by 1,050 · see citing works
Self-citationNagahara, A. H., Merrill, D. A., Coppola, G., Tsukada, S., Schroeder, B. E., Shaked, G. M., Wang, L., Blesch, A., Kim, A., Conner, J. M., et al. (2009) · Nature Medicine · doi:10.1038/nm.1912 · Cited by 1,034 · see citing works
Self-citationFischer, W., Wictorin, K., Björklund, A., Williams, L., Varon, S. S., & Gage, F. H. (1987) · Nature · doi:10.1038/329065a0 · Cited by 1,024 · see citing works
Levi‐Montalcini, R., & Hamburger, V. (1951) · Journal of Experimental Zoology · doi:10.1002/jez.1401160206 · Cited by 958 · see citing works
Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease
Blurton-Jones, M. M., Kitazawa, M., Martínez‐Coria, H., Castello, N. A., Müller, F.-J., Loring, J. F., Yamasaki, T. R., Poon, W. W., Green, K. N., & LaFerla, F. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901402106 · Cited by 858 · see citing works
Marks, W. J., Bartus, R. T., Siffert, J. O., Davis, C. S., Lozano, A. M., Boulis, N. M., Vitek, J. L., Stacy, M. A., Turner, D. A., Verhagen, L., et al. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70254-4 · Cited by 685 · see citing works
Self-citationThe Nucleus Basalis Magnocellularis Cholinergic System: One Hundred Years of Progress
Wenk, G. L. (1997) · Neurobiology of Learning and Memory · doi:10.1006/nlme.1996.3757 · Cited by 284 · see citing works
Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC
Bankiewicz, K. S., Forsayeth, J., Eberling, J. L., Sánchez‐Pernaute, R., Pivirotto, P., Bringas, J., Herscovitch, P., Carson, R. E., Eckelman, W. C., Reutter, B. W., et al. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.05.005 · Cited by 282 · see citing works
Tuszynski, M. H., U, H., Amaral, D., & Gage, F. H. (1990) · Journal of Neuroscience · doi:10.1523/jneurosci.10-11-03604.1990 · Cited by 281 · see citing works
Self-citationScott, S. A., Mufson, E. J., Weingartner, J. A., Skau, K., & Crutcher, K. A. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-09-06213.1995 · Cited by 264 · see citing works
Kordower, J. H., Herzog, C. D., Dass, B., Bakay, R. A. E., Stansell, J., Gasmi, M., & Bartus, R. T. (2006) · Annals of Neurology · doi:10.1002/ana.21032 · Cited by 251 · see citing works
Self-citationA phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease
Rafii, M. S., Baumann, T. L., Bakay, R. A. E., Ostrove, J. M., Siffert, J., Fleisher, A. S., Herzog, C. D., Barba, D., Pay, M., Salmon, D. P., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.09.004 · Cited by 223 · see citing works
Self-citationMufson, E. J., Ma, S. Y., Dills, J. L., Cochran, E. J., Leurgans, S. E., Wuu, J., Bennett, D. A., Jaffar, S., Gilmor, M. L., Levey, A. I., et al. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10122 · Cited by 197 · see citing works
Kordower, J. H., Winn, S. R., Liu, Y. T., Mufson, E. J., Sladek, J. R., Hammang, J. P., Baetge, E. E., & Emerich, D. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10898 · Cited by 193 · see citing works
Human nerve growth factor improves spatial memory in aged but not in young rats
Markowska, A. L., Koliatsos, V., Breckler, S., Price, D., & Olton, D. S. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-08-04815.1994 · Cited by 188 · see citing works
Reduction of cortical TrkA but not p75NTR protein in early‐stage Alzheimer's disease
Counts, S., Nadeem, M., Wuu, J., Ginsberg, S. D., Saragovi, H. U., & Mufson, E. J. (2004) · Annals of Neurology · doi:10.1002/ana.20233 · Cited by 183 · see citing works
Early BDNF Treatment Ameliorates Cell Loss in the Entorhinal Cortex of APP Transgenic Mice
Nagahara, A. H., Mateling, M., Kovács, I., Wang, L., Eggert, S., Rockenstein, E. M., Koo, E. H., Masliah, E., & Tuszynski, M. H. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5195-12.2013 · Cited by 176 · see citing works
Self-citationSomatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration
Chen, K., & Gage, F. H. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-04-02819.1995 · Cited by 165 · see citing works
Tuszynski, M. H., Roberts, J. A., Senut, M., U, H. S., & Gage, F. H. (1996) · PubMed · Cited by 164 · see citing works
Self-citationEight Years of Clinical Improvement in MPTP-Lesioned Primates After Gene Therapy With AAV2-hAADC
Hadaczek, P., Eberling, J. L., Pivirotto, P., Bringas, J., Forsayeth, J., & Bankiewicz, K. S. (2010) · Molecular Therapy · doi:10.1038/mt.2010.106 · Cited by 158 · see citing works
Martı́nez-Serrano, A., Fischer, W., & Björklund, A. (1995) · Neuron · doi:10.1016/0896-6273(95)90051-9 · Cited by 157 · see citing works
Hypophagia is induced by intracerebroventricular administration of nerve growth factor
Williams, L. R. (1991) · Experimental Neurology · doi:10.1016/0014-4886(91)90143-z · Cited by 141 · see citing works
Winkler, J., Ramirez, G. A., Kuhn, H. G., Peterson, D. A., Day-Lollini, P. A., Stewart, G. R., Tuszynski, M. H., Gage, F. H., & Thal, L. J. (1997) · Annals of Neurology · doi:10.1002/ana.410410114 · Cited by 138 · see citing works
Self-citationGoedert, M., Fine, A., Dawbarn, D., Wilcock, G. K., & Chao, M. V. (1989) · Molecular Brain Research · doi:10.1016/0169-328x(89)90011-9 · Cited by 130 · see citing works
Conner, J. M., Darracq, M. A., Roberts, J., & Tuszynski, M. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1941 · Cited by 116 · see citing works
Self-citationConner, J. M., Muir, D., Varon, S. S., Hagg, T., & Manthorpe, M. (1992) · The Journal of Comparative Neurology · doi:10.1002/cne.903190310 · Cited by 105 · see citing works
Self-citationTuszynski, M. H., & Gage, F. H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.10.4621 · Cited by 99 · see citing works
Self-citationMandel, R. J., Gage, F. H., Clevenger, D. G., et al. (1999) · Experimental Neurology · doi:10.1006/exnr.1998.6961 · Cited by 72 · see citing works
Holtzman, D. M., Li, Y., Chen, K., Gage, F. H., Epstein, C. J., & Mobley, W. C. (1993) · Neurology · doi:10.1212/wnl.43.12.2668 · Cited by 67 · see citing works
Lin, C., Heron, P. M., Hamann, S. R., & Smith, G. M. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.04.053 · Cited by 28 · see citing works
Conner, J., & Varon, S. (1996) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(95)00151-4 · Cited by 26 · see citing works
Self-citationWong, A. W., Yeung, J., Payne, S. C., et al. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.03.004 · Cited by 17 · see citing works
Smithson, L. J., Krol, K. M., & Kawaja, M. D. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.014 · Cited by 5 · see citing works
NGF promotes synovial nerve sprouting
Killock, D. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.6 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease
Khan, S., Barve, K. H., & Kumar, M. S. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200528142429 · Cited by 820 · see citing works
“In an effort to test the ability to degenerate neurons in AD towards a nervous system growth factor (NGF), Tuszynski et al. (2015) subjected ten patients with early AD with NGF gene ex vivo or in vivo therapy [101].”
BackgroundMethodNot just amyloid: physiological functions of the amyloid precursor protein family
Müller, U. C., Deller, T., & Korte, M. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.29 · Cited by 634 · see citing works
Tet-On Systems For Doxycycline-inducible Gene Expression
T. Das, A., Tenenbaum, L., & Berkhout, B. (2016) · Current Gene Therapy · doi:10.2174/1566523216666160524144041 · Cited by 434 · see citing works
“Specifically, nerve growth factor (NGF) has been delivered in the brain of patients with Alzheimer disease either via direct intracerebral injection of an AAV vector or via transplantation of genetically-modified cells [20] and neurturin, a member of the glial cell linederived neurotrophic factor (GDNF) family ligands…”
MethodAdeno-Associated Virus-Based Gene Therapy for CNS Diseases
Hocquemiller, M., Giersch, L., Audrain, M., Parker, S., & Cartier, N. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.087 · Cited by 291 · see citing works
Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment
Folch, J., Petrov, D., Ettcheto, M., Abad, S., Sánchez-López, E., García, M. L., Olloquequi, J., Beas-Zarate, C., Auladell, C., & Camins, A. (2016) · Neural Plasticity · doi:10.1155/2016/8501693 · Cited by 270 · see citing works
Rafii, M. S., Tuszynski, M. H., Thomas, R. G., Barba, D., Brewer, J. B., Rissman, R. A., Siffert, J., Aisen, P. S., & for the AAV2-NGF Study Team (2018) · JAMA Neurology · doi:10.1001/jamaneurol.2018.0233 · Cited by 219 · see citing works
Self-citationViral vectors for therapy of neurologic diseases
Choudhury, S. R., Hudry, E., Maguire, C. A., Sena-Esteves, M., Breakefield, X. O., & Grandi, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.013 · Cited by 190 · see citing works
Reimagining cholinergic therapy for Alzheimer’s disease
Giacobini, E., Cuello, A. C., & Fisher, A. (2022) · Brain · doi:10.1093/brain/awac096 · Cited by 187 · see citing works
Adult neurogenesis and neurodegenerative diseases: A systems biology perspective
Horgusluoglu, E., Nudelman, K., Nho, K., & Saykin, A. J. (2017) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32429 · Cited by 174 · see citing works
Wang, J., Li, Z., Pan, M., Fiaz, M., Hao, Y., Yan, Y., Sun, L., & Yan, F. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114539 · Cited by 161 · see citing works
Yang, J., Wu, S., Hou, L., Zhu, D., Yin, S., Yang, G., & Wang, Y. (2020) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2020.06.013 · Cited by 154 · see citing works
Self-citationKatsouri, L., Lim, Y. M., Blondrath, K., Eleftheriadou, I., Lombardero, L., Birch, A. M., Mirzaei, N., Irvine, E. E., Mazarakis, N. D., & Sastre, M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1606171113 · Cited by 146 · see citing works
Neurotrophins and Proneurotrophins: Focus on Synaptic Activity and Plasticity in the Brain
Gibon, J., & Barker, P. A. (2017) · The Neuroscientist · doi:10.1177/1073858417697037 · Cited by 115 · see citing works
Bartus, R. T., & Johnson, E. M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.03.027 · Cited by 97 · see citing works
AAV ablates neurogenesis in the adult murine hippocampus
Johnston, S., Parylak, S. L., Kim, S., Mac, N., Lim, C., Gallina, I., Bloyd, C., Newberry, A., Saavedra, C. D., Novak, O., et al. (2021) · eLife · doi:10.7554/elife.59291 · Cited by 87 · see citing works
Tanaka, H., Nakatani, T., Furihata, T., Tange, K., Nakai, Y., Yoshioka, H., Harashima, H., & Akita, H. (2018) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b01084 · Cited by 82 · see citing works
Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound
Stavarache, M. A., Petersen, N., Jurgens, E. M., Milstein, E. R., Rosenfeld, Z. B., Ballon, D. J., & Kaplitt, M. G. (2019) · Journal of Neurosurgery · doi:10.3171/2017.8.jns17790 · Cited by 76 · see citing works
Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain
Murlidharan, G., Crowther, A., Reardon, R. A., Song, J., & Asokan, A. (2016) · JCI Insight · doi:10.1172/jci.insight.88034 · Cited by 72 · see citing works
Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm
Josephy-Hernandez, S., Jmaeff, S., Pirvulescu, I., Aboulkassim, T., & Saragovi, H. U. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.08.004 · Cited by 54 · see citing works
Pickart, L., Vasquez-Soltero, J., & Margolina, A. (2017) · Brain Sciences · doi:10.3390/brainsci7020020 · Cited by 51 · see citing works
Gene Therapy Strategies for Alzheimer's Disease: An Overview
Alves, S., Fol, R., & Cartier, N. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.017 · Cited by 45 · see citing works
Spilman, P. R., Corset, V., Gorostiza, O., Poksay, K. S., Galvan, V., Zhang, J., Rao, R., Peters-Libeu, C., Vincelette, J., McGeehan, A., et al. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-151046 · Cited by 39 · see citing works
Ding, X.-W., Li, R., Geetha, T., Tao, Y.-X., & Babu, J. R. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165858 · Cited by 36 · see citing works
Fitzgerald, G. S., Chuchta, T. G., & McNay, E. C. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14160 · Cited by 22 · see citing works
- Authors
- Tuszynski, M. H., Yang, J. H., Barba, D., U, H.-S., Bakay, R. A. E., Pay, M. M., Masliah, E., Conner, J. M., Kobalka, P., Roy, S., & Nagahara, A. H.
- Affiliations
- University of California San Diego (US)
- Department of Neurosurgery, University of California, San Diego, La Jolla
- Rush University Medical Center (US)
- Corresponding author
- Tuszynski, Mark H.
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-10-01
- Volume
- 72
- Issue
- 10
- Pages
- 1139
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4944824
- OpenAlex
- W1961744561
- Cited by
- 287
- References
- 36
- Citations by year
- 2026: 9 · 2025: 24 · 2024: 25 · 2023: 24 · 2022: 18 · 2021: 29 · 2020: 20 · 2019: 30 · 2018: 36 · 2017: 30 · 2016: 39 · 2015: 3
- FWCI
- 26.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging (AG043416, P01AG010435, AG1035, U01AG043416, P50AG005131)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- nerve growth factor, gene therapy, Alzheimer's disease, cholinergic neurons, axonal sprouting, neuronal hypertrophy, adeno-associated virus vectors, tau pathology, neurodegeneration, gene transfer safety, neuroprotection, neurotrophin signaling, early Alzheimer's disease, ex vivo gene transfer, in vivo gene delivery, long-term gene expression
- MeSH terms
- Aged, Alzheimer Disease, Autopsy, Brain, Female, Humans, Male, Middle Aged, Nerve Degeneration, Neurons, Genetic Therapy, Gene Transfer Techniques, Nerve Growth Factor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
