Methods for diagnosis and treatment of Bloom's syndrome

Details Methods for diagnosis and treatment of Bloom's syndrome Methods for diagnosis and treatment of Bloom's syndrome

1998-10-20

2001-04-24

Achutamurthy, Ponnathapu (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

Reexamination Certificate

active

06221643

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention is based upon the discovery by the inventors of the gene associated with Bloom's syndrome (“BS”), the “BLM gene” or “BLM”, and a novel protein encoded by this gene. The discovery of the BLM gene and the protein encoded by the gene will have important implications in the diagnosis and treatment of BS, the recognition of carriers of mutations at BLM, and more broadly in the development of new cancer diagnostics and therapeutics.
BS is a rare autosomal recessive trait characterized clinically by growth deficiency, a sun-sensitive telangiectatic erythema of the face, immunodeficiency, and male infertility (German, J.
Medicine
72:393-406 (1993)). Somatic cells from persons with BS are characterized by a striking genomic instability, and display an increased frequency of chromosome abnormalities (breaks, gaps and rearrangements) and inter- and intramolecular exchanges, including sister-chromatid exchanges (Ray, J. H. and German, J. (1983) The cytogenetics of the “chromosome-breakage syndromes.” In: German J. (ed.) Chromosome mutations and neoplasia. Alan R. Liss, New York, pp. 135-168). The hypermutability of BS cells is responsible for the benign and malignant neoplasms in BS patients that arise at unusually early ages and in excessive numbers (German, 1993, supra).
Complementation analyses have established that a single locus, designated BLM, is mutated in BS (Weksberg, R., et al.
Am. J. Hum. Genet
. 42:816-824 (1988)). The BLM locus has been assigned to human chromosome 15 (McDaniel, L. D., and Schultz, R. A.
Proc. Natl. Acad. Sci. USA
89:7968-7972 (1992)), and regionally mapped to chromosome band 15q26.1 based upon tight linkage to FES by homozygosity mapping (German, J., et al.
Proc. Acad. Natl. Sci. USA
91:6669-6673 (1994)). Prior to the present invention, however, the BLM gene had not been identified.
SUMMARY OF THE INVENTION
The present invention provides a method for diagnosing BS in a subject comprising detecting the presence of two mutated BLM genes or the absence of a wild type BLM gene in nucleic acid of the subject. The present invention also provides a method for determining whether a subject is a carrier of a mutated BLM gene comprising detecting the presence of a mutated BLM gene in nucleic acid of the subject.
The present invention further provides one or more single-stranded nucleic acid probes which specifically hybridize to the wild type BLM gene or the mutated BLM gene, and mixtures thereof, which may be formulated in kits, and used for diagnosing BS or determining whether a subject is a carrier of the mutated BLM gene.
In addition, the present invention provides an antibody immunoreactive with a wild type BLM protein, as well as an antibody immunoreactive with a mutant BLM protein, which may be formulated in kits, and used for diagnosing BS or determining whether a subject is a carrier of the mutated BLM gene.
The present invention also provides a method for treating or preventing the onset of BS in a subject in need of such treatment or prevention comprising the delivery and expression of a functional BLM gene into a sufficient number of cells of the subject to treat or prevent the onset of BS in the subject. A stem cell which expresses the BLM gene introduced therein through viral transduction, homologous recombination or transfection is also provided by the invention.
The present invention further provides a recombinant viral vector for treating a defect in the BLM gene in a target cell comprising (a) the nucleic acid of or corresponding to at least a portion of the genome of a virus, which portion is capable of directing the infection of the target cell, and (b) a BLM gene operably linked to the viral nucleic acid and capable of being expressed as a functional gene product in the target cell.
The present invention still further provides a purified and isolated nucleic acid encoding an enzymatically active BLM protein, a vector comprising this nucleic acid, a cell stably transformed with this vector, as well as a method for producing recombinant, enzymatically active BLM protein. A purified, enzymatically active BLM protein is also provided by the present invention.
Finally, the present invention provides a vector and an embryonic stem cell each of which comprises a mutated BLM gene, a non-human, transgenic animal whose germ and somatic cells contain a mutated BLM gene sequence introduced into said animal, or an ancestor thereof, at an embryonic stage, as well as a method for producing the non-human, transgenic animal.
Additional objects of the invention will be apparent from the description which follows.


REFERENCES:
Puranam et al. Cloning and characterization of RECQL, a potential human homologue of theEscherichia coliDNA helicase RecQ. J. Biol. Chem. (1994) 269(47):29838-45, Nov. 1994.*
Gangloff et al. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase, Mol. Cell Biol. (Dec. 1994) 14(12):8391-8.*
Umezu et al.Escherichia coliRecQ protein is a DNA helicase. PNAS (Jul. 1990) 87(14):5363-7.

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