Swine defective for transmission of porcine endogenous retrovirus and uses thereof

Abstract

Miniature swine whose genomes contain sequences characteristic of pig endogenous retrovirus genes but which are non-infectious to humans are disclosed as sources of organs, tissues and cells for introduction into human recipients afflicted with diseases, or at risk of diseases, whose etiology involves the presence of inadequately functioning organs and for which xenotransplantation of such organs, tissues and cells would have a palliative effect. Methods of producing such animals and for screening animals for the desired properties are also disclosed.

Description

[0001] This application claims the priority of U.S. Provisional Application Ser. No. 60 / 243695, filed 27 Oct. 2000, U.S. Provisional Application Ser. No. 60 / 182965, filed 16 Feb. 2000, and U.S. Provisional Application Ser. No. 60 / 177003, filed 19 Jan. 2000, the disclosures of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention is directed to inbred swine free of pig endogenous retrovirus (PERV) sequences that are capable of capable of contributing toward viruses infecting human cells and to methods of xenotransplantation of organs from such swine into humans and to methods of screening such swine at high stringency to insure their freedom from human tropic endogenous retrovirus components otherwise infectious to humans as well as methods for the production of such swine. BACKGROUND OF THE INVENTION [0003] Organ transplantation is the established treatment for end-stage organ disease. However, there exists a worldwide short...

AI Technical Summary

Benefits of technology

[0014] It is an object of the present invention to provide a swine breed, and methods of producing the same, which breed does not produce porcine endogenous retrovirus (PERV) that can infect human cells, thereby having a unique advantage over other swine breeds with respect to its microbiological safety for xenotransplantation.

[0017] It is also an object of the present invention to provide such a breed having a more appropriate size of full grown adults to serve as solid organ donors for humans, plus a long period, as much as 25 years, of medical and quality information on a closed herd of such animals and animals exhibiting immunological tolerance.

Problems solved by technology

However, there exists a worldwide shortage of organs available for transplantation.

In the USA alone, there are currently approximately 60,000 people waiting for organ transplants and 4000 die every year before a transplant can be performed [1] with the waiting list artificially constrained in size due to the limited type and number of donor organs available.

Organisms benign in their natural host can cause significant morbidity in a zoonotic scenario.

Secondly, the consequences of transmission of an organism might not stop solely with the xenograft recipient.

Thus the control and monitoring of recurrent infection during xenotransplantation procedures is viewed as an important public health issue [2].

In addition, although it may be possible to detect an infection of the recipient by a microorganism quickly and before manifestations of disease become apparent, effective treatments may not have been developed because in almost all cases no previous infections by this organism will have been documented.

The greatest risk of infection is probably with those organisms that have an ability to be transferred as an asymptomatic latent entity within the organ.

Consequently, if the presence of a particular provirus in the DNA of a germ-line cell places the offspring at a selective disadvantage it would not be expected to survive over evolutionary time periods and this ERV is not expected in the ongoing gene pool.

Individual ERV loci also tend to be replication defective due to mutations present in their genome.

However, the potential exists for individual defective loci to interact by complementation and recombination to form infectious virus.

Approximately 50 copies of the virus are present in every cell, and as such cannot be completely removed by conventional breeding techniques.

However, pathogens such as ERV that are transmitted through the germ-line would not be eliminated and the recent evidence cited above demonstrates that certain PERVs are capable of infecting human cells so that one of the potential risks from the use of pig organs is the transmission of such pathogens.

Studies into PERV are complicated by the predominance of defective copies of the virus, which are very closely related to replication competent copies of the virus.

The possible lifelong screening currently required clearly places not only a significant monetary cost on the xenotransplantation procedure, but also a practical burden on the patient due to the repeated monitoring procedures.

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