Use of Modified Pyrimidine Compounds to Promote Stem Cell Migration and Proliferation

Abstract

This invention provides cells and methods for stimulating proliferation and migration of endogenous and exogenous mammalian stem cells in vivo and in vitro. The invention provides reagents and methods for efficiently proliferating mammalian stem cells in an animal in need thereof and producing stem cells that can be re-introduced into an animal in need thereof to alleviate neurological and corporal disorders.

Description

[0001]This invention was made with support from the U.S Government through the National Institutes of Health, grant no. R03-AG19874. The government has certain rights in this invention.[0002]This application is related to U.S. Provisional Patent Applications, Ser. No. 60 / 348,473, filed Jan. 14, 2002, and Ser. No. 60 / 357,783, filed Feb. 19, 2002, and Ser. No. 60 / 376,257, filed Apr. 29, 2002, and Ser. No. 60 / 381,138, filed May 8, 2002, and Ser. No. 60 / 404,361, filed Aug. 19, 2002, and Ser. No. 60 / 430,381, filed Dec. 2, 2002, the disclosures of each of which are expressly incorporated by reference herein.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]This invention relates to methods for stimulating proliferation and migration of mammalian stem cells in vivo and in vitro and cells produced by those methods. In particular, the invention provides reagents and methods for efficiently proliferating stem cells in an animal in need thereof and producing stem cells that can b...

AI Technical Summary

Benefits of technology

[0023]This invention provides methods for stimulating proliferation, migration or both proliferation and migration of mammalian stem cells in vivo and in vitro and cells produced by those methods. In particular, the invention provides reagents and methods for efficiently proliferating stem cells in an animal in need thereof and producing stem cells that can be re-introduced into an animal in need thereof to alleviate neurological disorders.

Problems solved by technology

However, such treatments have faced significant hurdles that have yet to be substantially overcome.

Such diseases, including Alzheimer's disease, Huntington's chorea and Parkinson's disease, have been linked to neuronal degeneration at specific locations in the brain, leading to the inability of the brain region to synthesize and release neurotransmitters that are vital to neuronal signaling.

Degeneration in the basal ganglia can lead to motor deficits.

Administration of pharmaceutical compositions has been the main treatment for CNS dysfunction though this type of treatment has complications, including the limited ability to transport drugs across the blood-brain barrier, and drug-tolerance acquired by patients to whom these drugs are administered for long periods.

In practice, however, significant limitations have been found in this technique as well.

First, cells used for transplantation that carry cell surface molecules of a differentiated cell from a donor can induce an immune reaction in the recipient, a problem that is exacerbated by the physical damage caused by injection of cells directly into the affected area of the brain.

However, although the brain is considered an immunologically privileged site, some rejection of even fetal tissue can occur.

Therefore, the ability to use heterologous fetal tissue is limited by tissue rejection and the resulting need for immunosuppressant drug administration.

The use of large quantities of aborted fetal tissue presents other difficulties as well.

In addition, it may be unlikely that an adequate and constant supply of fetal tissue would be available for transplantation.

There is also the added problem of the potential for contamination during fetal tissue preparation.

Since this tissue may already be infected with a bacteria or virus, expensive diagnostic testing is required for each fetus used.

Even comprehensive diagnostic testing might not uncover all infected tissue.

For example, there can be no guarantee that a sample is HIV-free, because antibodies to the virus are generally not present until several weeks after infection.

In addition to fetal tissue, there are other potential sources of tissue for neurotransplantation, including cell lines and genetically engineered cell types, but both sources have serious limitations.

However, there still exists a risk of inducing an immune reaction with these cells.

In addition, retrovirus mediated transfer may result in other cellular abnormalities.

Also, cell lines produced by retrovirus-mediated gene transfer have been shown to gradually inactivate their transferred genes following transplantation and further may also not achieve normal neuronal connections with the host tissue.

Currently available transplantation approaches suffer from significant drawbacks.

The inability in the prior art of the transplant to fully integrate into the host tissue, and the lack of availability of suitable cells in unlimited amounts from a reliable source for grafting are significant limitations of neurotransplantation.

The results have generally been poor because, among many considerations, the dissociation of clusters of NSCs is known to cause immediate senescence of NSCs and increase the vulnerability of NSCs in culture.

Thus, significant problems with the use of NSCs to ameliorate neurological deficits remain.

The problems described above in using NSCs to remedy neurological deficits of the brain also apply to neurological deficits in other tissues, such as the eye, and corporal deficits.

Images