Posted 14 July 2004
Used neuroantibody approach based on the local secretion of recombinant antibodies
in transgenic mice, to neutralize the activity of NGF (nerve growth factor).
For anti-NGF transgenic mouse, the variable regions of light and heavy chains of
the anti-NGF monoclonal antibody αD11 were linked to human κ and γ1
constant regions, yielding the chimeric human/rat antibody αD11, and placed
under control of the human cytomegalovirus (CMV) early region promoter. Linearized
DNA was microinjected into pronucleus of C57BL/6 × SJLF2 hybrid mouse eggs, and
the injected eggs were reintroduced into foster pseudopregnant females of an outbred
strain. Mice expressing functional anti-NGF antibodies (anti-NGF mice) were obtained
by crossing mice expressing the light chain (CMV-VK αD11) with mice expressing
the heavy chain (CMV-VH αD11).
Mutation: B6.SJL-Tg (AD11-VH) Tg (AD11-VK)
Promoter: HCMV early promoter region
Background: C57BL/6 x SJL
Age dependent and progressive neuronal degeneration characterized by: cholinergic
loss in the basal forebrain and nucleus of Meynert; accumulation of phosphorylated
tau and tangles in hippocampal and cortical neurons. Accumulation of ßAmyloid in
the hippocampus. Over-expression of inflammatory markers. Impairment of synaptic
plasticity in cortex and hippocampus. Tg mice express a neutralizing anti-NGF recombinant
antibody, in which the levels of antibodies are three orders of magnitude higher
in adult than in newborn mice.
Starting from 4 months, age dependent deficits in spatial and recognition memory
(Radial maze, Morris water maze, object recognition test)
International Application: WO2000IT00321, 07/28/2000
USA application: 10/049,306, 06/05/2002
F. Giuliani or Simona Capsoni, PhD
Lay Line Genomics S.p.A.
c/o San Raffaele Scientific Park
Bldg B Floor 3
Via di Castel Romano 100
00128 Roma, Italy
Phone: Company at + 39 06 80319053 or S. Capsoni at + 39 06 80319038 (direct)+39
Mice available for collaboration agreements, service for fee activity, non exclusive
Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gonfloni S, Rossi G,
Berardi N, Cattaneo A. Phenotypic knockout of nerve growth factor in adult transgenic
mice reveals severe deficits in basal forebrain cholinergic neurons, cell death
in the spleen, and skeletal muscle dystrophy. J Neurosci. 2000 Apr 1 ;
Capsoni S, Giannotta S, Stebel M, Garcia AA, De Rosa R, Villetti G, Imbimbo BP,
Pietra C, Cattaneo A. Ganstigmine and donepezil improve neurodegeneration in AD11
antinerve growth factor transgenic mice. Am J Alzheimers Dis Other Demen.
2004 May-Jun ;19(3):153-60.
Capsoni, S, Giannotta, S, Cattaneo, A Early events in Alzheimer-like neurodegeneration
in anti-nerve growth factor transgenic mice. Brain Aging 2: 24, 2002. Abstract
Capsoni, S, Giannotta, S, Cattaneo, A. Beta-amyloid plaques in a model for sporadic
Alzheimer's disease based on transgenic anti-nerve growth factor antibodies. Mol
Cell Neurosci 21: 15, 2002.
Capsoni, S, Giannotta, S, Cattaneo A Nerve growth factor and galantamine ameliorate
early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad
Sci USA 99: 12432, 2002.
Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A. Alzheimer-like
neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad
Sci U S A. 2000 Jun 6 ; 97(12):6826-31.
Pesavento, E, Capsoni, S, Domenici, L, Cattaneo, A. Acute cholinergic rescue of
synaptic plasticity in the neurodegenerating cortex of anti-nerve-growth-factor
mice. Eur J Neurosci 15: 1030, 2002.