Research Article A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease Michael S. Rafii a,z , Tiffany L. Baumann b,z , Roy A. E. Bakay c,y , Jeffrey M. Ostrove b , Joao Siffert b , Adam S. Fleisher a , Christopher D. Herzog b , David Barba a , Mary Pay a , David P. Salmon a , Yaping Chu c , Jeffrey H. Kordower c , Kathie Bishop b , David Keator d , Steven Potkin d , Raymond T. Bartus b, * ,z a Department of Neurosciences, University of California, San Diego, CA, USA b Ceregene, Inc., San Diego, CA, USA c Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA d University of California, Irvine, CA, USA Abstract Background: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the po- tential to restore function and to protect degenerating cholinergic neurons in Alzheimer’s disease (AD), but safe and effective delivery has proved unsuccessful. Methods: 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 ad- eno-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. Results: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imag- ing and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. Conclusions: 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. Ó 2013 The Alzheimer’s Association. All rights reserved. Keywords: Neurotrophic factors; Translational R&D; Gene therapy; Neuroprotection; Neurorestoration; Nucleus basalis of Meynert; Cholinergic neurons; Nerve growth factor 1. Introduction Alzheimer’s disease (AD) continues to represent a sig- nificant and serious unmet medical need. Cholinesterase in- hibitors are the primary treatment option for patients with AD, although their effects are merely palliative, providing modest symptomatic improvement for some, but not all, patients. Moreover, no treatment to date has slowed the rate of disease progression of AD. Nerve growth factor (NGF) is an endogenous neurotro- phic factor that, based on extensive research involving a J. Siffert is now at Avanir Pharmaceuticals, A.S. Fleisher is now at Ban- ner Alzheimer’s Institute, T.L. Baumann and K. Bishop are now at Isis Phar- maceuticals, and R.T. Bartus is now at RTBioconsultants, Inc. Conflicts of Interest: R.T. Bartus, T.L. Baumann, C.D. Herzog and J.M. Ostrove are consultants to Sangamo Biosciences, the company that acquired Ceregene, including all rights to AAV2-NGF (CERE-110). All other authors have nothing to disclose. y Deceased. z Contributed equally to the construction and writing of the article. *Corresponding author. Tel.: 1858-720-0607; Fax: 858-792-7524 E-mail address: bartus@rtbioconsultants.com 1552-5260/$ - see front matter Ó 2013 The Alzheimer’s Association. All rights reserved. http://dx.doi.org/10.1016/j.jalz.2013.09.004 Alzheimer’s & Dementia - (2013) 1–11