Methods for diagnosing, preventing, and treating...

Details Methods for diagnosing, preventing, and treating... Methods for diagnosing, preventing, and treating...

1999-05-25

2001-04-03

Sisson, Bradley L. (Department: 1655)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

C536S023100, C536S024310, C536S024330, C435S183000, C435S252300, C435S320100

Reexamination Certificate

active

06210950

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally to novel methods of diagnosing, preventing, and treating specific diseases which are caused by a combination of genetic and environmental factors. One such disease exemplified is schizophrenia.
BACKGROUND OF THE INVENTION
The term “schizophrenia” was introduced by Bleuler in the beginning of this century to encompass a dissociation or disruption of thought processes, along with a dichotomy among thought, emotion, and behavior [Bleuler,
Translation J. Zinkin
, New York: International University Press (1950)]. The current definition of schizophrenia includes a break with reality that is usually manifested as hallucinations, delusions, or disruption in thought processes [Carpenter et al.,
Medical Progress
, 330:681-690 (1994)]. At present the nationally accepted definition for the diagnosis of schizophrenia is contained in Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Washington, D.C (1994): American Psychiatric Association, hereby incorporated by reference in its entirety.
Schizophrenia is a clinical syndrome that has a profound influence on public health. The symptoms for schizophrenia begin early in life, and continues for most patients throughout their lives. An estimate of the direct and indirect costs of schizophrenia was thirty-three billion dollars for 1990 in the United States alone [Carpenter et al., 1994, supra]. Indeed, one of every forty dollars spent for total heath care expenditures in the United States is spent on treating schizophrenia [Rupp et al.,
Psychiatric Clin. North Am
., 16:413-423 (1993)]. Furthermore, estimates have been made suggesting that up to 50% of the homeless American population is schizophrenic [Bachrach, In:
Treating the Homeless Mentally Ill
, Washington, D.C., American Psychiatric Press, 13-40, Lamb et al. ed. (1992)].
The genetic factors in schizophrenia, though clearly documented to be present, are not simple [Carpenter and Buchanan,
N. Engi. J. Med
., 330:681-689 (1994); Gottesman,
Clin. Genet
., 46:116-123 (1994)]. Schizophrenia is, at least in part, a neurodevelopmental disorder, a birth defect in which the brain has been subtly damaged during development [Carpenter and Buchanan,
N. Engl. J. Med
., 330:681-689 (1994); Weinberger,
Arch. Gen. Psychiatry
, 44:660-669 (1987); Brixey et al.,
J. Clin. Psychol
., 49:447-456 (1993)]. Evidence of this damage is seen both at autopsy [Kovelman and Scheibel,
Biol. Psychiatry
, 19:1601-1621 (1984); Bogerts et al.,
Arch. Gen. Psychiatry
, 42:784-791 (1985); Jakob and Beckman,
J. Neural Transm
., 65:303-326 (1986); Brown et al.,
Arch. Gen. Psychiatry
, 43:36-42 (1986); Benes and Bird,
Arch Gen Psychiatry
, 44:608-616 (1987); Colter et al.,
Arch Gen Psychiatry
, 44:1023 (1987); Altshuler et al.,
Arch. Gen. Psychiatry
, 47:1029-1034 (1990); Pakkenberg,
Schizophr. Res
., 7:95-100 (1992); Bogerts,
Schizophr. Bull
., 19:431-445 (1993); Shapiro,
Schizophr. Res
., 10:187-239 (1993)] and by neuroimaging [Jeste et al.,
Br. J. Psychiatry
, 153:444-459 (1988); Suddath et al.,
Am. J. Psychiatry
, 146:464-472 (1989); Suddath et al.,
N. Engl. J. Med
., 322:789-794 (1990); DeLisi et al.,
Biol. Psychiatry
, 29:159-175 (1991); Breier et al.,
Arch. Gen. Psychiatry
, 49:921-926 (1992); O'Callaghan et al.,
J. R. Soc. Med
., 85:227-231 (1992); Bogerts et al.,
Biol. Psychiatry
, 33:236-246 (1993); Andreasen et al.,
Science
, 266:294-298 (1994)]. The pattern of this brain damage and the presence of minor congenital abnormalities point to an insult occurring during the second trimester of fetal development [Bracha et al.,
Biol. Psychiatry
, 30:719-725 (1991); Bracha et al.,
Am. J. Psychiatry
, 149:1355-1361 (1992); Green et al.,
Psychiatry Res
., 53:119-127 (1994)]. Epidemiological studies have documented a season-of-birth effect by which schizophrenics are more frequently born during winter and early spring than during other seasons [Boyd et al.,
Schizophr. Bull
., 12:173-186 (1986); Kendell and Adams,
Br. J. Psychiatry
, 158:758-763 (1991); O'Callaghan et al.,
Br. J. Psychiatry
, 158:764-769 (1991)].
Also, individuals exposed to an influenza epidemic [Mednick et al.,
Arch. Gen. Psychiatry
, 45:189-192 (1988); Barr et al.,
Arch. Gen. Psychiatry
, 47:869-874 (1990); O'Callaghan et al.,
Lancet
., 337:1248-1250 (1991); Murray et al.,
J. Psychiatr. Res
., 26:225-235 (1992); Adams et al.,
Br. J. Psychiatry
, 163:522-534 (1993)] or famine [Susser and Lin,
Arch. Gen. Psychiatry
, 49:983-988 (1992)] during their second trimester of fetal development have increased risk of later developing schizophrenia, according to some studies but not others [Kendell,
Arch. Gen. Psychiatry
, 46:878-882 (1989); Crow and Done, Br.
J. Psychiatry
, 161:390-393 (1992)]. This has suggested that an environmental effect such as dietary deficiency, virus infection [Kirch,
Schizophr. Bull
., 19:355-370 (1993)], vitamin deficiency, or effect of cold weather may be acting during fetal development.
Linkage mapping studies in schizophrenia have been difficult. Recently, some studies [Straub et al.,
Nature Genet
., 11:287-293 (1995); Schwab et al.,
Nature Genet
., 11:325-327 (1995); Moises et al.,
Nature Genet
., 11:321-324 (1995)] have supported a gene locus on chromosome 6 (6p24-22, near the HLA region) as having an effect in schizophrenia; other studies gave little or no support to a marker in this region [Wang et al.,
Nature Genet
., 10:41-46 (1995); Mowry et al.,
Nature Genet
., 11:233-234 (1995); Gurling et al.,
Nature Genet
., 11:234-235 (1995); Antonarakis et al.,
Nature Genet
., 11:235-236 (1995)]. At best this locus appeared to be involved in only about 15-30% of families [Straub et al., 1995, supra]. Also, some evidence for loci on chromosomes 3 [Pulver et al.,
Am. J. Med. Genet
., 60:252-260 (1995), 8 [Pulver et al.,
Am. J. Med. Genet
., 60:252-260 (1995); Kendler et al.,
Am. J. Psych
. 153:1534-1540 (1996), 9 [Coon et al.,
Biol. Psychiatry
, 34:277-289 (1993); Moises et al.,
Nature Genet
., 11:321-324 (1995)] and 22 [Coon et al.,
Am. J. Med. Genet
., 54:72-79 (1994); Pulver et al.,
Am. J. Med. Genet
., 54:3-43 (1994)]have been reported. In addition, two polymorphic markers very close to the gene encoding dihydrofolate reductase (DHFR) on chromosome 5q, D5576 and D5S39, gave very high lod scores (as high as 6.49, i.e. odds of about 3 million to one in favor of genetic linkage versus chance occurrence) in 7 British and Icelandic schizophrenia families studied [Schwab et al.,
Nat. Genet
. 11:325-327 (1997); Straub et al., Molec Psychiatr. 2:148-155 (1997)]. However, this result could not be confirmed in studies of numerous other families.
There could be several reasons for this difficulty. First, there may be more than one gene involved, (locus heterogeneity). Second, the genetic factor(s) may be common in the population (high disease allele frequency), thus diminishing the power of linkage studies [Terwilliger and Ott,
Handbook of Human Genetic Linkage
, Baltimore: Johns Hopkins Univ. Pr., 181 (1994)]. Third, the correct genetic model may be unknown [Owen,
Psychol. Med
., 22:289-293 (1992)]. Any or all of these factors could diminish the power of a linkage study sufficiently to make success very difficult [Terwilliger and Ott, 1994, supra].
Thus the current (developmental) model for schizophrenia is that genetic and environmental factors cause brain damage in a fetus that later develops schizophrenia. However, the genetic and environmental factors have not been identified. Also, extensive linkage and association studies have failed to identify genes determining schizophrenia.
Indeed, schizophrenia appears to be just one of a family of developmental disorders whose cause has not been identified. Other such developmental disorders are defined by the Diag

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