Posted 14 July 2004

Transgene:

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

Phenotype

Neuropathological analysis:

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.

Behavioral:

Starting from 4 months, age dependent deficits in spatial and recognition memory (Radial maze, Morris water maze, object recognition test)

Patents:

International Application: WO2000IT00321, 07/28/2000
USA application: 10/049,306, 06/05/2002

Availability

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 06 80319065
Email: f.giuliani@laylinegenomics.com or s.capsoni@laylinegenomics.com

Mice available for collaboration agreements, service for fee activity, non exclusive license agreements.

Reference

Primary:

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 ; 20(7):2589-601. Abstract

Associated:

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. Abstract

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. Abstract

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. Abstract

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. Abstract

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. Abstract