Preparative regimen for engraftment, growth and differentiation of non-hematopoeitic cells in vivo after transplantation

Abstract

The invention relates to methods of obtaining an expanded population of mammalian ex vivo cells and / or for treating a mammalian subject by (a) administering to a subject an effective amount of an agent that confers a growth disadvantage to at least a subset of endogenous cells at the site of engraftment; (b) administering to the subject an effective amount of a mitogenic stimulus for the ex vivo cells; and (c) administering the ex vivo cells to the subject, wherein the ex vivo cells engraft at the site and proliferate to a greater extent than the subset of endogenous cells, to repopulate at least a portion of the engraftment site with the ex vivo cells. The repopulated cells can be harvested for further use or be left at the engraftment site of a subject to be treated. The invention also provides methods of treating brain injury in a subject by engrafting ex vivo cells at the site of injury.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 890,444 which was filed on Feb. 16, 2007, which is incorporated herein by reference in its entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]NOT APPLICABLEREFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK[0003]NOT APPLICABLEFIELD OF THE INVENTION[0004]This invention relates to methods of cell transplantation therapy in which the subject is administered an effective amount of an agent that confers a growth disadvantage to at least a subset of endogenous cells at the site of engraftment.BACKGROUND OF THE INVENTION[0005]Orthotopic whole organ transplantation is expensive and invasive. Moreover, there is an acute shortage of donor organs. Accordingly, cell transplantation has been considered as a potential alternative ...

AI Technical Summary

Benefits of technology

[0016]In other embodiments, the mitogenic stimulus may comprise one or more growth factors for the cell type to be engrafted. In some embodiments, the growth factors are one, two, three or more growth factors selected from the group consisting of HGF, EGF, FGF, VEGF, NGF, Il-6, TNF-alpha, CTNF, R-spondin 1, Noggin, and TWEAK. In other embodiments, the administered ex vivo cells comprise, contain, or include a heterologous gene that increases their intrinsic proliferation capacity or survival. In some embodiments, the mitogenic stimulus can comprise a biological agent, antibody or peptide factor that increases the proliferation capacity of the donor cells or comprise a procedure that deliberately injures the engraftment site to enable entry and integration of the transplanted cells into the host parenchyma and / or to provide a compensatory growth signal for the ex vivo cells. In some further embodiments, the procedure is a surgical resection, portal vein branch ligation, portal vein embolism by chemotherapeutic agents or toxins, radiofrequency ablation, radiosurgical ablation, or high frequency ultrasonic ablation of the a portion of the donor organ.

Problems solved by technology

Orthotopic whole organ transplantation is expensive and invasive.

Moreover, there is an acute shortage of donor organs.

Cell transplantation has been around for two decades but has not been clinically very useful because even when primary or stem cells can engraft in organs they often cannot selectively proliferate or repopulate the intended organ.

Accordingly, cell transplantation without a preparative regimen of is ineffective because of poor engraftment of the transplanted cells in the host organ.

Administration of growth factors alone cannot offer selective proliferative / growth advantage to the transplanted cells over the residual host cells and have not been used clinically.

In practice, however, cancer patients are rarely considered for OLT because of the long waiting lists for donor liver.

Although the study demonstrated the long-term safety of HT, only partial correction of the metabolic disorder was achieved, because of the lack of proliferation of the engrafted donor hepatocytes.

While it has been established that HT can be employed safely in humans, its applicability remains limited by:(i) a critical shortage of donor hepatocytes,(ii) the number of hepatocytes that can be transplanted safely, without causing portal hypertension,(iii) the inability of the transplanted hepatocytes to proliferate in the host liver, and(iv) lack of a noninvasive method to evaluate the repopulation of transplanted hepatocytes in the liver.

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