SV-40 derived DNA constructs comprising exogenous DNA sequences

Details SV-40 derived DNA constructs comprising exogenous DNA sequences SV-40 derived DNA constructs comprising exogenous DNA sequences

1997-01-15

2000-07-18

Chambers, Jasemine C.

Chemistry: molecular biology and microbiology

Virus or bacteriophage, except for viral vector or...

4353201, 435325, 435455, 536 235, C12N 701, C12N 1586, C12N 510

Patent

active

060906081

DESCRIPTION:

BRIEF SUMMARY
RELATED APPLICATIONS

This application is the U.S. National Phase Application of PCT/US95/05595 with an international filing date of May 4, 1995 and which is a continuation-in-part application of Israel Patent Application No.: 109558, filed May 4, 1990, entitled "SV40 Derived DNA Constructs Comprising Exogenous DNA Sequences," the teachings of which are hereby incorporated by reference, in their entirety.


FIELD OF THE INVENTION

The present invention is generally directed to gene therapy, and particularly to gene therapy of hemopoietic diseases. More specifically, the present invention relates to DNA constructs comprising exogenous DNA encoding a therapeutic protein product, DNA sequences derived from SV40 and additional genetic regulatory elements sufficient for the expression of the exogenous DNA in cells of a mammal, thereby enabling the obtention, once the constructs are inserted therein, of transfected mammalian cells which are capable of expressing the exogenous DNA encoding the therapeutic product.


BACKGROUND OF THE INVENTION

The concept of gene therapy first arose during the 1960s and early 1970s. As it became clear that active genes may be transferred into mammalian cells, the idea that diseases may be treated at the genetic level started to develop. In many hereditary diseases the patient suffers from low or altogether absent production of a critical protein. The rationale behind gene therapy approach is that the missing protein may be supplied by the appropriate gene, encoding the specific protein, introduced into the patient's cells. This rationale may be applied to any protein of therapeutic value, for example the production of tumor suppressors in the treatment of cancer. Furthermore, this approach is also applicable to the production of regulatory macromolecules such nucleic acids which would bind to a biologically active protein or block its expression.
There are two basic strategies, generally ex vivo and in vivo gene therapy. Ex vivo gene therapy may be described as genetically modifying cells obtained from a patient, or from a different source, and using the modified cells to treat a pathological condition which will be improved by the long-term or constant delivery of the therapeutic product produced by the modified cells. Treatment includes also the re-introduction, where applicable, e.g. in the case of erythroid cells, of the modified cells, obtained from either the patient or from a different source, into the patient. In vivo gene therapy, on the other hand, refers to direct in vivo delivery of the therapeutic gene into the appropriate tissue of the patient. In vivo delivery may be achieved by a variety of techniques, such as intravenous delivery, direct injection into muscles, inhalation into the lung, etc.
With respect to the specific case of treating .beta.-thalassemia, i.e. gene therapy with the normal .beta.-globin gene, a number of developments have been achieved. The molecular defects of .beta.-thalassemia have been well characterized and seem amenable to genetic correction. In .beta.-thalassemia patients, deficient or absent .beta.-globin gene synthesis causes the production of poorly hemoglobinized, defective erythrocytes resulting in severe anemia. Effective gene therapy requires safe, efficient, and stable transfer of globin genes into human hemopoietic stem cells and subsequent high-level gene expression in maturing erythroid cells. Prior to clinical trials, it was necessary to develop experimental laboratory and animal models. Such models would enable the detailed study of the target cells and the regulation of the inserted gene.
One of the major problems in developing a model for gene therapy of .beta.-thalassemia is the difficulty in introducing the cloned plasmid DNA into hemopoietic cells. Several procedures have been developed to circumvent this difficulty. However, none has been successful in achieving gene delivery and expression. For example, attempts have been made to insert the .beta.-globin gene into retrovirus-derived vectors and subsequently to infect m

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