Human disease modeling using somatic gene transfer

Abstract

The invention provides a system for modeling neurodegenerative and other diseases through somatic gene transfer. In addition, methods of multiple gene transfer, disease analysis and drug testing are provided for.

Description

[0001] This invention provides a system for modeling neurodegenerative and other diseases through somatic gene transfer. In addition, methods of multiple gene transfer, disease analysis and drug testing are provided for.BACKGROUND TO THE INVENTION[0002] Numerous methods of gene transfer are known in the art, and are not reviewed in any great detail here. Suffice it to say that in general, methods of gene transfer in vitro are well known and have been practiced for several decades. Methods of in vivo gene transfer are much more recent, but have been successfully applied in such contexts as gene therapy efforts to overcome genetic disorders, and in disease modeling efforts, such as the production of germ-line transgenic animal models, such as gene knockout mice or transgenic mice and other animals expressing heterologous genes. For a global review of Parkinsons and other Neurodegenerative Disorders see Neurodegenerative Dementias:Clinical Features and Pathological Mechanisms, (edited ...

AI Technical Summary

Benefits of technology

"This patent is about a system for modeling neurodegenerative diseases by using somatic gene transfer. The invention provides methods for knocking out single genes or introducing multiple genes in animal models. The limitations of current methods include inducing terminal illnesses in animal models, difficulty in inducing multiple gene knockouts, and slow time scales for animal maturation. The invention aims to address these limitations and provide techniques for modeling neurodegenerative diseases and drug testing. The patent also describes the use of gene transfer to study the effects of mutant genes associated with neurodegenerative diseases. The DNA constructs used in the invention are packaged into recombinant adeno-associated virus (AAV) vectors. The invention provides a system for modeling neurodegenerative diseases and drug testing using somatic gene transfer."

Problems solved by technology

The limitations to such methods include the possibility of inducing terminal illnesses in the animal models, such that either non-viable fetuses are produced, or limited life-span animals are produced.

In addition, the effects of multiple gene knockouts or transgenes are extremely difficult to simulate in such systems, due to the complex temporal, gene regulatory and interaction effects in such systems.

Furthermore, the germ-line transgenic models currently available tend to provide data on a very slow time scale, and such efforts as drug modeling and disease analysis are delayed by the time-scale of transgenic animal maturation.

Interestingly, while the fly model mimics many cardinal features of PD, including age-dependent loss of dopamine neurons, Lewy-like inclusion bodies, and motor deficits (Feany and Bender, 2000), mammalian models have been less successful or consistent.

Although two of the transgenic lines effectively targeted the SN by using the tyrosine hydroxylase (TH) promoter (Rathke-Hartlieb et al., 2001; Matsuoka et al., in press), others were less successful in producing robust expression of .alpha.-syn in the SN (Masliah et al., 2000; van der Putten et al., 2000; Kahle et al., 2000).

a. The ability to more precisely control the location to which the genes are transferred (i.e. spatial control of gene expression);

b. The ability to more precisely analyze the temporal effects of transferred genes at specific times in the development of otherwise normal organisms (i.e. temporal control of gene expression);

c. The ability to evaluate the effects of expression of combinations of multiple transgenes, which in a germline transgenic animal would be difficult if not impossible to achieve due to diseases which might prevent the animal model from maturing to the age-appropriate state for modeling onset of a particular, complex human disease, such as Alzheimer's.

Images