Fetal globin inducing factor

Details Fetal globin inducing factor Fetal globin inducing factor

1997-12-05

2001-02-06

McKelvey, Terry (Department: 1636)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

C530S324000, C530S350000

Reexamination Certificate

active

06184343

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acids that encode fetal globin inducing factor and to fetal globin inducing factor. The invention also relates to methods for altering globin expression by the regulation of globin transcription.
BACKGROUND OF THE INVENTION
Oxygen is transported throughout multicellular animals through the function of hemoglobin. The most primitive of these oxygen-carrying molecules, or globins, is a single polypeptide of about 150 amino acid residues and is utilized in worms, insects, and primitive fish. In higher adult vertebrates two types of globin chains exist. These chains are referred to as the &agr; and &bgr; globins and make up a tetrameric hemoglobin molecule composed of two &agr; and two &bgr; chains, or &agr;
2
&bgr;
2
. Through a series of gene duplications during evolution, other globin chains also exist and exhibit developmental and stage specific expression. These other globins include &ggr; globin which is specifically expressed in the fetus to produce an &agr;
2
&ggr;
2
hemoglobin. This fetal hemoglobin exhibits higher affinity for oxygen than adult &agr;
2
&bgr;
2
hemoglobin. Another globin chain arising during evolution is the &dgr; globin which gives rise to the minor hemoglobin &agr;
2
&dgr;
2
found in adult primates. Finally, an &egr; globin also exists which results in another embryonic form of hemoglobin having the composition &agr;
2
&egr;
2
.
Abnormalities in the structure or in the rate of synthesis of the various globin chains result in a variety of different pathological conditions which can be classified into two distinct groups (Stamatoyannopoulos and Nienhuis,
Molecular Basis of Blood Diseases
, Stamatoyannopoulos et al. (eds.), Philadelphia pp. 108-136, 1994; D. J. Weatherall,
Molecular Basis of blood Diseases
, Stamatoyannopoulos et al. (eds.), Philadelphia pp. 161-195, 1994; and Bunn, H. F.,
Molecular Basis of Blood Diseases
, Stamatoyannopoulos et al. (eds.), Philadelphia pp. 208-244, 1994).
The first classification is where structural abnormalities of &agr; or &bgr; globin genes exist. These abnormalities are called hemoglobinopathies. There are over 500 different mutations of &agr; or &bgr; globin genes producing abnormal hemoglobins. The most common hemoglobinopathy is the sickle hemoglobin or hemoglobin S (Hb S) which represents the substitution of valine for glutamic acid in position six of the &bgr; globin subunit. The sickle cell gene is frequent among Black people; about eight to ten percent of African-Americans carry the Hb S gene while in certain populations of Africa, like in Nigeria, twenty-five percent of the population carries sickle cell trait. There are about 120,000 new cases of sickle cell disease born each year. It is estimated that the prevalence of homozygous Hb S patients in the United States is between 60,000 and 80,000. Sickle cell disease is a severe disease characterized by frequent painful crises, hemolytic anemia and severe organ damage due to intravascular sickling. The life span of these patients is significantly decreased.
Evidence now indicates that elevated levels of fetal hemoglobins (Hb F) attenuate the severity of sickle cell disease. As is well known, Hb S molecules tend to form long, intracellular polymers upon deoxygenation. Physiological effects of sickle cell mutations are due, in large part, to abnormalities in the rheological properties of blood. The rate of sickle cell hemoglobin polymerization is largely dependent on the concentration of Hb S in the red cell. The presence of fetal hemoglobin in sickle red cells affects Hb S polymerization by decreasing the concentration of the abnormal molecule and, most importantly, by failing to participate in polymer formation. In addition to this biochemical evidence, genetic evidence similarly indicates that high levels of Hb F have therapeutic effects in sickle cell disease. For example, compound heterozygotes inheriting a sickle cell gene and a gene for hereditary persistence of fetal hemoglobin have no clinical manifestations when Hb F exceeds twenty-five percent of total hemoglobin content (75% of hemoglobin in these patients is Hb S). Similar observations exist for persons who carry the combination of the sickle cell gene and a condition called &dgr;&bgr; thalassemia which is associated with high levels of Hb F.
The levels of Hb F required for therapeutic benefit in sickle cell disease have been investigated in several studies. In a prospective study, Hb F levels in excess of ten percent were associated with fewer episodes of aseptic necrosis, while levels greater than twenty percent were associated with fewer painful crises and pulmonary complications. In a large prospective study of the natural history of sickle cell disease, the frequency of painful crises was found to be inversely proportional to the square of the Hb F level. These results indicate that even modest elevations in Hb F can yield therapeutic benefits. It is generally accepted that production of over twenty-five percent fetal hemoglobin in the red cell can cure sickle cell disease.
The second classification is where abnormalities in globin chain synthesis exist. These abnormalities are called &agr;, &bgr;, or &dgr;&bgr; thalassemia syndromes. An example of these abnormalities is the &bgr; thalassemia syndromes. Beta (&bgr;) thalassemia genes are common among people of Mediterranean and Asian descent. About 100,000 patients with homozygous thalassemia, or combinations of &bgr; thalassemia with abnormal hemoglobins, are born each year in this area of the world. In &bgr; thalassemia there is either a total absence or a severe deficiency of &bgr; globin gene. However, &agr; chain production continues at normal levels. These excess &agr; globin chains accumulate and precipitate within erythroblasts resulting in ineffective erythropoiesis and cell death, both of which are characteristic of the thalassemia syndromes.
Precipitation of &agr; chains in circulating erythrocytes and consequential membrane damage is responsible for the hemolytic syndrome. Patients with homozygous &bgr; thalassemia survive beyond the period of the switch from fetal to adult globin formation because some level of Hb F production continues in the adult stage of development. Sufficient &ggr; gene expression occurs in only a small proportion of erythroblasts. Cells which contain adequate levels of Hb F survive and thereby provide red cells which are released in the periphery. The efficiency of &ggr; globin production in erythroblasts of patients with &bgr; thalassemia clearly determines the severity of their clinical course. It is accepted that any increase of fetal hemoglobin will have therapeutic effects in &bgr; thalassemia syndromes. Production of over twenty-five percent of fetal hemoglobin per cell can cure the disease of patients with homozygous &bgr; thalassemia.
Attempts have been made to augment the expression of fetal hemoglobin for the therapeutic treatment of sickle cell disease or homozygous &bgr; thalassemia (Blau and Stamatoyannopoulos,
Hematology Trends
'93, Lechner et al. (eds.), Stuttgart-New York, pp 144-158, 1993). For example, 5-azacytidine induces fetal hemoglobin in animals and patients with thalassemia or sickle cell disease. However, its use was discontinued because it has been shown that this drug is carcinogenic. Hydroxyurea, a cytotoxic drug used in cancer chemotherapy, has also been shown to induce fetal hemoglobin in experimental animals. This compound kills mature erythroid cells and induces a fast downstream differentiation of immature cells. Treatment of sickle cell patients with hydroxyurea results in induction of fetal hemoglobin which reaches therapeutic levels in a small proportion of patients. However, induction of fetal hemoglobin occurs only when blood cytotoxicity appears as measured by decreased white blood cell counts. Furthermore, issues related to the wisdom of life long treatment with a cytotoxic drug which may also be carcinogenic remain especially for the treatment of children. Further, a large portion of patients respo

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