Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-02-14
2001-05-08
Sisson, Bradley L. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06228594
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to the gene, and mutations thereto, that are responsible for the disease hereditary hemochromatosis (HH). More particularly, the invention relates to the identification, isolation, and cloning of the DNA sequence corresponding to the normal and mutant HH genes, as well as the characterization of their transcripts and predicted gene products. The invention also relates to methods and the like for screening for HH homozygotes and further relates to HH diagnosis, prenatal screening and diagnosis, and therapies of HH disease, including gene therapeutics, protein and antibody based therapeutics, and small molecule therapeutics.
2. Background of the Technology
Hereditary hemochromatosis (HH) is an inherited disorder of iron metabolism wherein the body accumulates excess iron. In symptomatic individuals, this excess iron leads to deleterious effects by being deposited in a variety of organs leading to their failure, and resulting in cirrhosis, diabetes, sterility, and other serious illnesses. Neither the precise physiological mechanism of iron overaccumulation nor the gene which is defective in this disease has been described.
HH is inherited as a recessive trait; in the current state of knowledge, homozygotes carrying two defective copies of the gene are affected by the disease. It is estimated that approximately 10% of individuals of Western European descent carry one copy of the HH gene mutation and that there are about one million homozygotes in the United States. HH, thus, represents one of the most common genetic disease mutations in individuals of Western European descent. Although ultimately HH produces debilitating symptoms, the majority of homozygotes have not been diagnosed. Indeed, it has been estimated that no more than a small fraction of affected individuals in the United States have been diagnosed with this condition.
The symptoms of HH are often similar to those of other conditions, and the severe effects of the disease often do not appear immediately. Accordingly, it would be desirable to provide a method to identify persons who may be destined to become symptomatic in order to intervene in time to prevent excessive tissue damage associated with iron overload. One reason for the lack of early diagnosis is the inadequacy of presently available diagnostic methods to ascertain which individuals are at risk, especially while such individuals are presymptomatic.
Although blood iron parameters can be used as a screening tool, a confirmed diagnosis often employs liver biopsy which is undesirably invasive, costly, and carries a risk of mortality. Thus, there is a clear need for the development of an inexpensive and noninvasive diagnostic test for detection of homozygotes in order to facilitate diagnosis in symptomatic individuals, provide presymptomatic detection to guide intervention in order to prevent organ damage, and for identification of heterozygote carriers.
The need for such diagnostics is documented, for example, in Barton, J. C. et al.
Nature Medicine
2:394-395 (1996); Finch, C. A.
West J Med
153:323-325 (1990); McCusick, V.
Mendelian Inheritance in Man
pp. 1882-1887, 11th ed., (Johns Hopkins University Press, Baltimore (1994));
Report of a Joint World Health Organization/Hemochromatosis Foundation/French Hemochroniatosis Association Meeting on the Prevention and Control of Hemochromatosis
(1993); Edwards, C. Q. et al.
New Engi J Med
328:1616-1620 (1993); Bacon, B. R.
New Engl J Med
326:126-127 (1992); Balan, V. et al.
Gastroenterology
107:453-459 (1994); Phatak, P. D. et al.
Arch Int Med
154:769-776 (1994).
Although the gene carrying the mutation or mutations that cause HH has previously been unknown, genetic linkage studies in HH families have shown that the gene that causes the disease in Caucasians appears to reside on chromosome 6 near the HLA region at 6p21.3 (Cartwright,
Trans Assoc Am Phys
91:273-281 (1978); Lipinski, M. et al.
Tissue Antigens
11:471-474 (1978)). It is believed that within this locus, a single mutation gave rise to the majority of disease-causing chromosomes present in the population today. See Simon, M. et al.
Gut
17:332-334 (1976); McCusick, V. supra. This is referred to herein as the “common” or “ancestral” or “common ancestral” mutation. These terms are used interchangeably. It appears that about 80% to 90% of all HH patients carry at least one copy of the common ancestral mutation which is closely linked to specific alleles of certain genetic markers close to this ancestral HH gene defect. These markers are, as a first approximation, in the allelic form in which they were present at the time the ancestral HH mutation occurred. See, for example, Simon, M. et al.
Am J Hum Genet
41:89-105 (1987); Jazwinska, E. C. et al.
Am J Hum Genet
53:242-257 (1993); Jazwinska, E. C. et al.
Am J Hum Genet
56:428-433 (1995); Worwood, M. et al.
Brit J Hematol
86: 863-866 (1994); Summers, K. M. et al.
Am J Hum Genet
45:41-48 (1989).
Several polymorphic markers in the putative HH region have been described and shown to have alleles that are associated with HH disease. These markers include the published microsatellite markers D6S258, D6S306 (Gyapay, G. et al.
Nature Genetics
7:246-339 (1994)), D6S265 (Worwood, M. et al.
Brit J Hematol
86:833-846 (1994)), D6S 105 (Jazwinska, E. C. et al.
Am J Hum Genet
53:242-257 (1993); Jazwinska, E. C. et al.
Am J Hum Genet
56:428-433 (1995)), D6S1001 (Raha-Chowdhury, R. et al.
Hum Molec Genet
3:2043-2046 (1994)), D6S1260 (Stone, C. et al.
Hum Molec Genet
4:1869-1874 (1995)) as well as additional microsatellite and single-nucleotide-polymorphism markers disclosed in co-pending U.S. patent application Ser. No.08/599,252, filed Feb. 9, 1996 (now issued as U.S. Pat. No. 5,705,343), which is a continuation-in-part of U.S. patent application Ser. No. 08/559,302, filed Nov. 15, 1995, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 08/436,074, filed May 8, 1995 (now issued as U.S. Pat. No. 5,753,438), the disclosures of which are hereby incorporated by reference in their entirety.
Although each of such markers may be of use in identifying individuals carrying the defective HH gene, crossing-over events have, over time, separated some of the ancestral alleles from the mutation that is responsible for RH, thereby limiting the utility of such surrogate markers. The limited diagnostic power of surrogate markers is obvious considering the fact that the frequency of the ancestral allele in the population is generally higher than the estimated frequency of the disease-causing mutation. The only exception is a marker designated 24d1, which has been disclosed in U.S. patent application Ser. No. 08/632,673, filed on Apr. 16, 1996 (now issued as U.S. Pat. No. 5,712,098). The ancestral allele of 24d1 has a population frequency that is consistent with the estimated frequency of the ancestral HH mutation. The desirability of identifying the gene responsible for HH has long been recognized due to the health benefits that would be available via gene-based diagnostics, which has an intrinsically higher predictive power than surrogate markers and may eventually lead to the identification and diagnosis of disease-causing mutations other than the ancestral mutation. In addition, identification of the HH gene would further our understanding of the molecular mechanisms involved in HH disease thereby opening new approaches for therapy. This goal has motivated numerous, but previously unsuccessful attempts to identify the HH gene.
These attempts have been made by a variety of methods. For example, genes known to be involved in iron transport or metabolism have been examined as candidates. An example of one unsuccessful attempt is the assignment of the ferritin heavy chain gene to Chromosome 6p, and subsequent exclusion of this gene on the basis of its precise localization outside of the HH region, and failure to find mutations in HH patients. See Dugast I. J. et al.
Genomics
6:204-211 (
Drayna Dennis T.
Feder John N.
Gnirke Andreas
Ruddy David
Thomas Winston J.
Bio-Rad Laboratories, Inc.
Pennie & Edmonds LLP
Sisson Bradley L.
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