Name:	CERE-110
Other Names:	Nerve Growth Factor Gene Therapy
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Viral-based gene delivery
Mechanisms:	NGF may reduce cholinergic cell loss in Alzheimer disease
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	There is abundant data that demonstrate cholinergic neuron function loss and cholinergic neuron cell death in Alzheimer disease. Nerve growth factor (NGF) has been shown to rescue cholinergic cell death in rats and primates. A phase 1 Alzheimer disease clinical trial of ex vivo delivery of nerve growth factor gene expressed in a retroviral vector has been completed (Tuszynski, 2005).
Role in Alzheimer's Disease:	NGF specifically targets basal forebrain cholinergic neurons, which release ACh in the cerebral cortex and hippocampus. Preclinical data in rats demonstrate that NGF prevented cholinergic neuron cell death (Hefti, 1986) and reversed age-related behavioral decline (Fischer, 1987). NGF gene therapy has been tested in rhesus monkeys (Tuszynski, 2005), and these studies demonstrated that NGF ameliorates cholinergic neuron atrophy and restores cholinergic axonal density in aged monkeys to levels observed in young monkeys. Dose escalation studies resulted in toxic secondary effects observed at any dose. Data from a Down syndrome mouse model showed that the increased expression of APP due to trisomy decreased NGF retrograde intra-axonal transport and caused degeneration of basal forebrain cholinergic neurons (Salehi, 2006). Phase I clinical trial NCT00087789 (ClinicalTrials.gov) is ongoing but not recruiting participants, being conducted at Rush University Medical Center in Chicago and UCSD. The open-label study involves 10 participants with mild-to-moderate AD. The 10 participants underwent cognitive testing, measures of activities of daily living, MRI scans and PET (positron emission tomography) scans. Increases in brain metabolism were observed in several cortical regions at six months and 12 months (p<0.05) in four participants as compared to other severity-matched individuals with AD suggesting a potential reversal of patterns typically observed in AD.
Pharmacological Role:	Nerve growth factor (NGF) has been implicated as a trophic agent in the survival and maintenance of basal forebrain cholinergic neurons. NGF receptor-positive basal forebrain neurons undergo marked cell atrophy and loss of neuropil staining in aged rats exhibiting impaired spatial learning and memory performance.
Side Effects:	As reported by the principal investigators, the administration of CERE-110 in Phase I is generally safe (if patients are anesthetized for stereotaxic surgery) and well tolerated, with no pain or weight loss. The phase 1 study of NGF gene therapy (Tuszynski, 2005) was completed safely in six of eight subjects. The first two patients were injected while awake. In these two patients, movement occurred during the procedure while the injection needle was in the brain, causing subcortical hemorrhage. The hemorrhage in these two patients resulted in pulmonary embolism and death in one subject, and exacerbation of dementia-associated aphasia in the second subject. All subsequent injections were performed in anesthetized subjects. A third subject experienced two syncopal episodes (fainting). Other adverse events reported included one incident each of knee effusion, wrist fracture, gout, and intermittent moderate lower back pain, which preceded the NGF treatment and did not change after treatment.
Evidence pro its efficacy:	NGF gene therapy reduced MMSE score decline by 51 percent as compared to the preoperative rate of cognitive decline. Two of six subjects showed improved MMSE scores. Similar reduction in decline rate was observed using ADAS-Cog. PET scans of NGF treated subjects showed an increase in glucose uptake by cortical neurons, using glucose analog fluorodeoxyglucose FDG.
Evidence con its efficacy:	There are potential risks associated with viral gene therapy. Gene delivery of NGF must be administered directly into the CNS to be effective on target neurons, requiring bilateral stereotaxic surgery on anesthetized subjects. Gene delivery must also be locally restricted to minimize risks of serious adverse effects that may result from broad distribution.
Companies:	Ceregene, Inc.
Notes:	A Phase II study initiated by Ceregene in April 2009 (ClinicalTrials.gov identifier: NCT00876863), a randomized, controlled study to evaluate CERE-110 in subjects with mild to moderate Alzheimer Disease is currently recruiting participants. See study details at CERE-110 Phase II. This entry was last updated November 18, 2009.

References

Bishop KM, Hofer EK, Mehta A, Ramirez A, Sun L, Tuszynski M, Bartus RT. Therapeutic potential of CERE-110 (AAV2-NGF): targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons. Exp Neurol. 2008 Jun;211(2):574-84. Abstract

Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. Abstract

Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, Conner J. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005 May 1; 11 (5):551-5. Abstract

Pedraza CE, Podlesniy P, Vidal N, Arévalo JC, Lee R, Hempstead B, Ferrer I, Iglesias M, Espinet C. Pro-NGF isolated from the human brain affected by Alzheimer's disease induces neuronal apoptosis mediated by p75NTR. Am J Pathol. 2005 Feb 1;166(2):533-43. Abstract

Fischer W, Wictorin K, Bjorklund A, Williams LR, Varon S, Gage FH. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature. 1987 Sep 3-9;329(6134):65-8. Abstract

Hefti F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci. 1986 Aug 1;6(8):2155-62. Abstract