Methods of diagnosis and treatment of meniere disease

Details Methods of diagnosis and treatment of meniere disease Methods of diagnosis and treatment of meniere disease

2000-05-25

2004-05-04

Winkler, Ulrike (Department: 1648)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S069100, C435S091200, C514S04400A, C536S025100, C536S025500, C536S024300

Reexamination Certificate

active

06730475

ABSTRACT:

BACKGROUND OF THE INVENTION
Hearing loss is a heterogeneous disorder that affects over 14 million people in the United States, with approximately 1 of every 1000 infants being affected by congenital deafness. An estimated one-half of congenital hearing loss cases are due to genetic causes (Bieber and Nance (1979)
Clinical Genetics—A Sourcebook for Physicians
, Jackson and Schimke, eds., Wiley, N.Y., vol. 60, pp. 443-461). More than 175 different forms of hereditary deafness have been characterized, including autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms (McKusick (1994)
Mendelian Inheritance in Man
, John Hopkins Univ. Press, Baltimore, Md.).
Genetic heterogeneity in hearing disorders both associated with other clinical anomalies (syndromic) and occurring as an isolated finding (nonsyndromic) indicates the involvement of a large number of genes in the complex development and function of the hearing process. Of the several hundred syndromic hearing loss disorders described (Gorlin et al. (1995)
Hereditary Hearing Loss and Its Syndromes
, Oxford Univ. Press, New York, N.Y.), only about 60 have been mapped to human chromosomes, with approximately half of these with characterized gene defects (Duyk et al.,
Nature Genet
. 2:5-8, 1992; Petit,
Nature Genet
. 14:385-391, 1996). The majority of congenital hearing disorders are nonsyndromic (Cohen and Gorlin (1995)
Hereditary Hearing Loss and its Syndromes
, Gorlin, Toriello and Cohen, eds., Oxford Univ. Press, New York, N.Y., vol. 60, pp. 9-21), but even fewer nonsyndromic disorders have been identified. This number is increasing through the study of consanguineous geographically isolated families. Over 40 human chromosomal loci associated with nonsyndromic hearing impairment have been identified, some with corresponding mouse mutants in the homologous region (Petit (1996), supra; Van Camp et al.,
Am. J Hum. Genet
. 60:758-764, 1997). However, to date, only a small number of nuclear genes responsible for nonsyndromic hearing impairment have been discovered. These include POU3F4 in DFN3 (de Kok et al.
Science
267:685-688, 1995); MYO7A in DFNB2 (Liu et al.,
Nature Genet
. 16:188-190, 1997; Weil et al.
Nature Genet
. 16:191-193, 1997) and DFN11 (Liu et al.,
Nature Genet
. 17:268, 1997); POU4F3 in DFNA15 (Vahava et al., Science 279:1950, 1998); PDS in DFNB4 (Li et al.,
Nature Genet
18:215, 1998); TECTA in both DFNA8 and DFNA11 (Verhoeven et al.,
Nature Genet
. 19:60, 1998); GJB2 in DFNB1 and DFNA3 (Kelsell et al.,
Nature
387:80-83, 1997).
The cause of many hearing disorders are still unknown. One such disorder is Meniere disease. Meniere disease is a syndrome in which hearing loss and imbalance problems co-occur. It is clinically characterized by recurrent episodes of vertigo associated with hearing loss and tinnitus with or without aural. Meniere disease is thought to be a multifactorial condition involving both genetic and environmental components.
SUMMARY OF THE INVENTION
The invention is based, at least in part, on the discovery that a nucleic acid and corresponding protein molecule (referred to herein as “COCH” or “COCH5B2”) are associated with the hearing disorder, Meniere disease. It was found that a missense mutation in the wild-type COCH5B2 gene, leads to an amino acid substitution in the COCH5B2 protein and plays a role in Meniere disease. Thus, mutated COCH5B2 molecules (also referred to as mtCOCH5B2 molecules) as described herein are useful in diagnosing hearing disorders such as Meniere disease. In addition, wild-type COCH5B2 (referred herein as “COCH” or “COCH5B2”) may be useful for the treatment of hearing disorders resulting from the expression and production of mtCOCH5B2. The properties of COCH5B2 are described in U.S. Ser. No. 09/394,264, which is incorporated herein by reference.
In general, the invention features a method of treating a subject at risk for (e.g., having or predisposed to) having Meniere disease. The method can include identifying an individual at risk for Meniere disease, and administering to the subject an effective amount of any of: COCH5B2 or a nucleic acid encoding it; an active fragment of COCH5B2 or a nucleic acid encoding it; an agonist of COCH5B2, e.g., a peptide or a peptomimetic analog; an antibody; or a small molecule, such that treatment of the subject occurs. Identification of an individual at risk for Meniere disease can be done in a number of different ways including: analyzing the family history of an individual; identifying an individual with vestibular dysfunction; identifying an individual by performing physical tests, e.g., otoscopy and pure tone audiometry; identifying an individual with a lesion in the COCH5B2 gene or mRNA; and/or identifying an individual with a mutant COCH5B2 protein sequence.
In a preferred embodiment, a method for treating a subject having Meniere disease comprises administering to the subject a COCH5B2 protein (SEQ ID NO:2), or portion thereof, such that treatment occurs. In another embodiment, Meniere disease can be treated by administering to the subject a nucleic acid encoding a COCH5B2 protein (SEQ ID NO:1 or SEQ ID NO3), or an active portion thereof, such that treatment occurs. The COCH5B2 molecule can be administered to a subject by any standard method, e.g., the COCH5B2 molecule can be administered by any of a number of different routes, e.g., intravenous, intradermal, subcutaneous, oral, transdermal (topical), or transmucosal administration.
In another aspect, the invention features a method of identifying an individual at risk for Meniere disease. The method includes detecting in the subject a genetic lesion(s) characterized by a mutation in the gene encoding a COCH5B2 protein (mtCOCH5B2 protein). In one embodiment, the lesion occurs in the COCH5B2 gene and a mutant mtCOCH5B2 protein is encoded. In another preferred embodiment, the lesion can be a deletion, insertion or substitution involving one or more nucleotides of the COCH5B2 gene, e.g., the lesion is a deletion or a substitution of nucleotide 151 of SEQ ID NO:3, e.g., the lesion is a substitution of the cytosine at nucleotide 151 of SEQ ID NO:3 to a thymidine. In another preferred embodiment, the lesion is a substitution, insertion or deletion of nucleotide 151 of SEQ ID NO:3, or a nucleotide which is 1, 2, 3, 5, 10 or more base-pairs on either side of nucleotide 151 of SEQ ID NO:3.
In one embodiment, the method includes contacting a sample, e.g., a cell sample, with a nucleic acid probe. In a preferred embodiment, the nucleic acid probe is capable of selectively binding a COCH5B2 nucleic acid sequence which contains a lesion, e.g., the probe only binds a COCH5B2 gene sequence which has a deletion, insertion or substitution. In a preferred embodiment, the probe binds a COCH5B2 sequence which has a substitution at nucleotide 151 of SEQ ID NO:3, e.g., the probe hybridizes to a COCH5B2 gene sequence that has a cytosine to thymidine substitution at nucleotide 151 of SEQ ID NO:3, e.g., the probe includes all or a portion of the nucleic acid sequence of SEQ ID NO:6 or the probe has the sequence 5′-tcctctgctcagggggc-3′ (SEQ ID NO:6).
In another embodiment, the method includes using a probe which can bind a mutant COCH5B2 protein which has a deletion, insertion or substitution at one or more amino acid residues. In a preferred embodiment, the probe can be a labeled probe or an antibody which is capable of selectively binding a mutant COCH5B2 protein. In another preferred embodiment, the labeled probe or antibody can selectively bind a COCH5B2 protein which has a substitution at amino acid residue 51 of SEQ ID NO:2, e.g., the proline at residue 51 of SEQ ID NO:2 is substituted with a serine; or the probe can selectively bind a mutant COCH5B2 protein which contains a deletion, insertion or substitution of 1, 2, 3, 4, 5 or more residues on either side of residue 51 of SEQ ID NO:2.
In a preferred embodiment, the method, as described above, can also be used in fetal or neonatal diagnosis.
Another aspect of the invention features a method for diagnosing

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