A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. Gene transfer, combined with stereotactic surgery,...

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Vydáno v:	Alzheimer's & dementia Ročník 10; číslo 5; s. 571
Hlavní autoři:	Rafii, Michael S, Baumann, Tiffany L, Bakay, Roy A E, Ostrove, Jeffrey M, Siffert, Joao, Fleisher, Adam S, Herzog, Christopher D, Barba, David, Pay, Mary, Salmon, David P, Chu, Yaping, Kordower, Jeffrey H, Bishop, Kathie, Keator, David, Potkin, Steven, Bartus, Raymond T
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.09.2014
Témata:	Aged Alzheimer Disease - diagnostic imaging Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer Disease - therapy Basal Nucleus of Meynert Dependovirus - genetics Feasibility Studies Female Genetic Therapy - methods Genetic Vectors Humans Immunohistochemistry Magnetic Resonance Imaging Male Middle Aged Nerve Growth Factor - genetics Neuropsychological Tests Neurosurgical Procedures Positron-Emission Tomography Stereotaxic Techniques Treatment Outcome Nucleus basalis of Meynert Neuroprotection Neurorestoration Nerve growth factor Translational R&D Cholinergic neurons Gene therapy Neurotrophic factors
ISSN:	1552-5279, 1552-5279
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Popis
Shrnutí:	Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1552-5279 1552-5279
DOI:	10.1016/j.jalz.2013.09.004