Multicellular living organisms and unmodified parts thereof and – Method of using a transgenic nonhuman animal in an in vivo...
Reexamination Certificate
1999-12-27
2002-12-03
Nguyen, Dave T. (Department: 1636)
Multicellular living organisms and unmodified parts thereof and
Method of using a transgenic nonhuman animal in an in vivo...
C800S008000, C800S009000, C800S012000, C800S013000
Reexamination Certificate
active
06489535
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of this invention is transgenic flies.
2. Background of the Invention
Adult onset neurodegenerative diseases are among some of the most devastating diseases currently afflicting mankind, at least in the developed nations of the world. Such diseases “are characterized by onset in adult life, chronic progressive course, distinct clinical phenotypes, specific cellular abnormalities involving subsets of neurons, and eventually fatal outcomes.” Price et al., Science (Nov. 6, 1998) 282: 1079-1083. Examples of neurodegenerative diseases include: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and the like. Currently, treatment of such diseases is limited to disease management and there are no cures. As such, there is much ongoing research that is aimed at the identification and development of new therapeutic agents which can at least slow, if not reverse, the progression of neurodegenerative diseases.
Critical steps in the identification and development of new therapeutic agents are: (a) the generation of candidate agents; and (b) screening of the candidate agents for efficacy (and safety). With the advent of combinatorial chemistry protocols, large numbers of potential compounds, known as libraries, can be rapidly generated. Such libraries serve as a collection of potential therapeutic agents. Following generation of a library of potential therapeutic agents, the library must be screened to identity the promising candidates.
For screening purposes, a number of in vitro high throughput screening protocols have been developed. However, these in vitro screening assays must be followed by in vivo screening assays. Since it is undesirable to immediately screen compounds that show promise from in vitro assays in humans, an important step in the identification of therapeutic agents for such neurodegenerative diseases is the screening of potential therapeutic compounds in non-human animal models. As such, non-human animal models of neurodegenerative diseases play an important role in the discovery of therapeutic agents for such diseases.
One type of non-human animal model that can be used for screening purposes to identify therapeutic agents for use in treating neurodegenerative diseases is a non-human mammalian model, e.g. primates, mice, etc. However, primates are expensive, difficult to use, and require a significant period of time prior to developing adult onset neurodegenerative symptoms. These factors make the use of primates as adult onset neurodegenerative animal models prohibitive. Transgenic mice suffer from analogous disadvantages, i.e. expense, slow reproduction time, and generation of small numbers of offspring.
As such, there is a need for additional animal models of adult onset neurodegenerative diseases. Of particular interest would be the development of an animal model having a relatively short life span and a rapid reproduction cycle characterized by the production of large numbers of offspring. Preferably, such an animal model should also be relatively simple and economic to maintain.
Relevant Literature
Patents of interest include: U.S. Pat. No. 4,670,388. Methods of preparing transgenic
Drosophila melanogaster
are disclosed in: Spradling, A. C., and Rubin, G. M. (1982). Science 218, 341-347; Brand & Perrimon, Development (1993) 118: 401-415; and Phelps & Brand, Methods (April 1998) 14:367-379. See also, Spradling A C, P Element Mediated Transformation in Drosophila: A Practical Approach (ed. D. D. Roberts, IRL Press, Oxford) (1986) pp 175-179. Articles disclosing drosophila that exhibit neurodegenerative phenotypes include: Buchanan and Benzer, Neuron (May 1993) 10: 839-850; Jackson et al, Neuron (September 1998) 21: 633-642; Kretzchmar et al., J. Neuroscience (Oct. 1, 1997) 17: 7425-7432; Marfany et al., J. Neurogenetics (1998) 12: 41-54; Min & Benzer, Current Biology (1997) 7:885-888; Rogina et al., Proc. Nat'l Acad. Sci. USA (June 1997) 94: 6303-6306; and Warrick et al., Cell (Jun. 12, 1998) 93: 939-949.
Articles describing non-human animal models for neurodegenerative diseases include: Price et al., Science (Nov. 6, 1998) 282:1079-1083.
SUMMARY OF THE INVENTION
Transgenic non-mammalian animals, e.g. flies, that exhibit an adult onset neurodegenerative phenotype, as well as methods for preparing the same, are provided. The subject transgenic animals are characterized in that they have a transgene stably integrated into their genome the expression of which in embryonic neuroblasts results in the adult onset neurodegenerative phenotype. In preferred embodiments, the transgene is a myb gene. Also provided are methods of screening compounds for activity with respect to adult onset neurodegeneration, particularly compounds having therapeutic activity with respect to adult onset neurodegenerative disease conditions.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Non-mammalian transgenic animals, particularly insects, e.g. flies, that exhibit adult onset neurodegeneration, as well as methods for their preparation, are provided. The subject transgenic animals are further characterized in that they comprise a stably integrated transgene which is expressed in embryonic neuroblasts, where the expressed product results in the observed adult onset neurodegenerative phenotype. In preferred embodiments, the transgene is a myb gene. Also provided are methods of using the subject non-mammalian transgenic animals to screen for compounds having activity with respect to adult onset neurodegeneration, particularly compounds that are therapeutic for neurodegenerative diseases. In further describing the subject invention, the transgenic animals and methods for their production will be detailed first, followed by a discussion of the screening methods of the subject invention.
Animal Models
In the broadest sense, the invention provides non-mammalian animal models that exhibit an adult onset neurodegenerative phenotype, where the phenotype results from a non-adult expression event. In other words, the phenotype of the animal models of the subject invention results from an expression event that occurs in the non-adult animal. The phenotype may result from a variety of different non-adult expression events, where the expression event may be the expression of a mutated gene, the failure of expression of a normally expressed gene, the expression of a transgene, and the like.
In many preferred embodiments, the subject invention provides non-mammalian transgenic animals (i.e. multi-cellular non-plant organisms) that have an adult onset neurodegenerative phenotype. In other words, the subject transgenic animals exhibit one or more phenotypic traits that characterize neurodegenerative disorders and occur in the adult organism (e.g. during the adult stage of the organism's life), where such traits include: impaired motor skills, impaired cognitive skills, reduced appetite, etc. As such, the subject animals are non-mammalian animal models for neurodegenerative disorders, particularly adult onset neurodegenerative disorders, such as: Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, stroke, and the like. The term transgenic animal is used broadly herein to refer to a non-plant multicellular organism at any stage of development, e.g. adult, fertilized eggs, embryos, larva, etc. Thus, a particular multicellular organism is a transgenic animal according to the subject invention no matter which stage of development it is at, so long as the animal exhibits the requisite adult onset neurodegenerative phenotypic characteristics that results from the correct spatial and temporal expression of the transgene stably integrated into its genome, as described in greater detail infra.
The transgenic animals of the subject invention are non-mammalian transgenic animals. Of particular interest are invertebrate transgenic animals, particularly members of the phylum arthropoda, and more particularly members of the class insecta. Of particular interest in many embodiments are tra
Fogarty Patrick
Lipsick Joseph
Bozicevic, Field & Francis
Field Bret E.
Nguyen Dave T.
Nguyen Quang
The Board of Trustees of the Leland Stanford Junior University
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