Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-10-10
2004-07-13
Jones, W. Gary (Department: 1634)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C435S006120, C435S091100, C435S091200
Reexamination Certificate
active
06762293
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the gene, and mutations, that are responsible for the disease hemochromatosis (MIM604653). In particular, the present invention provides for the presence of one or more mutations on the SLC11A3 gene which results in aberrant SLC11A3 mediated iron transport. The invention also relates to methods for screening for HH and to HH diagnosis, prenatal screening and diagnosis, and therapies of HH disease, including gene therapeutics, protein and antibody based therapeutics, and small molecule therapeutics. The invention further relates to drugs and therapies developed for the treatment of patients with HH or anemia.
2. Description of the Related Art
Over the years, several known genes involved in iron metabolism have been implicated in the pathology of HH. However, not all instances of HH patients can be explained by mutations in these genes. In particular, it is known that approximately 60-85% of all instances of HH in adult patients are indicated by homozygosity for the C282Y mutation in the HLA-H/HFE gene on Chromosome 6p. Compound heterozygosity accounts for an additional 10% of cases. It is also known that a form of juvenile hemochromatosis maps to chromosome 1q and that a single family was found with a mutation in a transferrin receptor gene (TFR2) on chromosome 7q. However, the remaining 5-15% of patients indicated with HH do not possess any mutations on the known genes. For example, Kato et al., describe a heterzygous A49T mutation in the 5_UTR of the H-subunit of ferritin without specifically delineating the contributions of this gene to the HH disease state (Am. J. Human Genetics 69: 191-7 (2001)). Clearly, neither the precise physiological mechanism of iron overaccumulation nor every gene which is defective in this disease has been described.
Hemochromatosis is an inherited disorder of iron metabolism wherein the body accumulates excess iron. In symptomatic individuals, excess iron is deposited in a variety of organs which leads to organ failure. Disease states such as cirrhosis, diabetes, sterility, and other serious illnesses occur as a result. It has also been discovered that HH can be inherited by a dominant or pseudo-dominant mode of inheritance. Heretofore, HH was believed to be inherited solely as a recessive trait. In particular, the prior art limits HH to patients having homozygotes carrying two defective copies of the gene.
Hemochromatosis is also one of the most common genetic disorders. The prior art estimates 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 HH ultimately produces debilitating symptoms, the majority of carriers 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.
Current diagnostic methods fail to comprehensively test for HH in individuals who are at risk, especially those individuals who are presymptomatic. Although blood iron parameters can be used as a screening tool, a confirmed diagnosis often employs a costly, invasive and high risk liver biopsy. An additional problem is that symptoms of HH are similar to those of other conditions and the severe effects of the disease tend not to appear immediately. Thus, there is a clear need for the development of an inexpensive and noninvasive comprehensive diagnostic test for detection of HH in order to facilitate comprehensive diagnosis and to provide comprehensive presymptomatic detection for the identification of HH carriers. Accordingly, comprehensive methods 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 are desirable.
U.S. Pat. No. 6,025,130 (“Thomas et al.”) describes a gene indicated for HH in the HLA region of Chromosome 6. Although Thomas et al. discloses a gene thought to cause HH, it does not provide for the remaining population of individuals who are symptomatic of HH but do not carry the mutation as taught by Thomas et al.
In the search for additional genes indicated for HH, one study generally concluded that HH can occur in adults who do not have pathogenic mutations in the hemochromatosis gene. See
N Engl J Med
341:725-32 (1999). In particular, the study found that members of a single family of Italian descent displayed symptoms of one or more distinct genetic diseases that cause a type of adult hereditary iron overload which was not associated with the known HH gene. The study, however, failed to provide for the gene hypothesized to cause the disease.
Another study relating to Zebrafish concluded that the gene ferroportin 1 (FNP1) may be involved in mammalian disorders of iron deficiency or overload.
Nature
, 403:17 (2000). In particular, the study focused on hypochromia caused by inadequate circulatory iron levels in embryonic Zebrafish. The study found that two independent autosomal recessive mutations caused hypochromia in the Zebrafish embryo. Mammalian homologues of these genes include SLC11A3.
However, the transversion site disclosed by the study differs from the present invention and is not believed to be responsible for HH. In particular, the study specifically teaches that a C-to-A transversion at codon 361 prematurely terminates translation of the SLC11A3 gene and that a G-to-T transversion at an undisclosed location results in a single amino acid change from Leucine to Phenylalanine. Additionally, the study fails to explain how the amino acid change affects the SLC11A3 protein. Accordingly, the study does not provide any motivation or suggestion to one of ordinary skill in the art to believe that a C-to-A transversion at codon 361 or a G-to-T transversion at an undisclosed location causes about 5-15% of all HH cases.
Genetic markers are also known for a mutation in recessive hemochromatosis. Diagnostic methods and kits for its determination are disclosed by U.S. Pat. Nos. 5,753,438 and 5,705,343.
U.S. Pat. No. 5,712,098 (“Tsuchibashi et al.”) also discloses recessive hereditary hemochromatosis diagnostic markers and diagnostic methods for same.
U.S. Pat. No. 5,674,681 (“Rothenberg”) discloses a method for identifying an individual having or predisposed to having hemochromatosis by detecting a mutation in the gene encoding a nonclassical MHC class I heavy chain. Rothenberg also discloses methods for treating recessive hemochromatosis involving administration of a “leczyme” having similar specificity for a carbohydrate ligand as the leczyme involved in the disease state. Clearly, the prior art fails to provide for the remaining 5-15% of patients indicated with HH who do not possess any mutations of known genes.
Accordingly, it would be highly desirable to identify, isolate, clone, and sequence the gene responsible for the remaining 5-15% of patients indicated with HH who do not possess any mutations of known genes. Such identification, isolation, cloning, and sequencing of the gene would enable the design and manufacture of products useful for the diagnosis and screening for HH. Identification of individuals affected with HH will allow initiation of this therapy, which can prevent symptoms, arrest progression of organ damage, and in some cases reverse pathology due to iron overload.
Moreover, such identification, isolation, and cloning of the gene would enable the study of the operation of the gene in the development of iron overload diseases, in general, and HH in particular. Further, it would be highly desirable to provide therapeutics for iron overload diseases, and HH disease in particular, as well as oxidative free radical diseases, reactions, and processes in general. The identification, isolation, sequencing, and cloning of the gene responsible for the remaining 5-15% of patients indicated with HH
Heutink Peter
Oostra Ben A.
van Duijn Cock M.
Erasmus University Rotterdam
Goldberg Jeanine
Jones W. Gary
Juneau Todd L.
Nath & Associates PLLC
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