Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
2000-11-28
2004-12-14
Rao, Manjunath (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C435S069100, C435S183000, C435S193000, C435S194000, C435S195000, C435S252300, C435S320100, C530S350000, C536S023200, C536S023400, C536S023500
Reexamination Certificate
active
06830913
ABSTRACT:
BACKGROUND OF THE INVENTION
ABC transporter proteins represent a large superfamily of proteins with conserved features in both prokaryotes and eukaryotes. ABC transporters catalyze ATP-dependent transport of endogenous or exogenous substrates across biological membranes (Borst, P., (1997)
Seminar in Cancer Biology
8:131-213) and/or allosterically modify the function of heterologous proteins (Higgins C F, 1995
, Cell
82:693-696). Several ABC transporters have been associated with clinically relevant phenotypes including the phenomenon of multidrug resistance (Ambudkar S. V. et al., (1999),
Annu. Rev. Toxicol
., 39:361-398), cystic fibrosis (Riordin J R et al., (1989)
Science
245:1066-1073), atherosclerosis (Brooks-Wilson A et al., (1999)
Nature Genetics
22:336-345), hyperinsulinemic hypoglycemia (Thomas P M et al., (1995)
Science
268:46-429), macular degeneration (Allikmets R et al., (1997)
Science
277:1805-1807), and adrenoleukodystrophy (Mosser J et al., (1993)
Nature
361:726-730) to name but a few. While the genes associated with these disease phenotypes have been identified to some degree, it is clear that a large number of putative ABC transporters exist in the human genome, as evidenced by the partial sequences noted in various EST databases (Allikmets et al., (1996)
Hum Mol Genet
5:1649-1655). However, the utility of such information is compromised by the absence of the full-length nucleotide sequence of the coding region of the relevant gene and its translated protein product.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of a novel ATP Binding Cassette (ABC) transporter family member, referred to herein as ABCB9 transporter nucleic acid and protein molecules The ABCB9 transporter molecules of the present invention are useful as targets for developing modulating agents to regulate a variety of cellular processes, particularly the transport of neurotoxic molecules, e.g., &bgr;-amyloid peptide (A&bgr;), across cell membranes or, e.g., the blood-brain barrier (BBB). Neurotoxic molecules such as &bgr;-amyloid peptide are involved in neurological disorders such as Alzheimer's disease (see, e.g., Goate et al. (1991)
Nature
349:704; Games et al. (1995)
Nature
373:523; and Suzuki et al. (1994)
Science
264:1336). Other neurological diseases involving toxic polypeptides include, e.g., prion diseases, Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Spinocerebellar Ataxia, Frontotemporal Dementia, etc. (Hardy et al. (1998)
Science
282:1075-1079; Wolozin et al. (2000)
Arch. Neurol
., 57:793-796).
Accordingly, modulation of amyloid-&bgr; protein export with a modulator of the human ABCB9 transporter would be expected to modulate amyloid deposition and thus, Alzheimer's disease.
In addition, the ABCB9 transporter molecules of the invention are useful as targets for developing modulating agents of multidrug resistance. Moreover, the molecules of the present invention are useful as diagnostic and therapeutic tools.
Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding ABCB9 transporter proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of ABCB9-encoding nucleic acids.
In one embodiment, an ABCB9 transporter nucleic acid molecule of the invention is at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more identical to the nucleotide sequence (e.g., to the entire length of the nucleotide sequence) shown in SEQ ID NO: 1 or 3, or a complement thereof.
In a preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown in SEQ ID NO: 1 or 3, or a complement thereof. In another embodiment, the nucleic acid molecule includes SEQ ID NO: 3 and nucleotides 1-298 of SEQ ID NO: 1. In another embodiment, the nucleic acid molecule includes SEQ ID NO: 3 and nucleotides 2597-3536 of SEQ ID NO: 1.
In another embodiment, an ABCB9 transporter nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO: 2. In a preferred embodiment, an ABCB9 transporter nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more homologous to entire length of the amino acid sequence of SEQ ID NO: 2.
In another preferred embodiment, an isolated nucleic acid molecule encodes the amino acid sequence of human ABCB9 transporter having the amino acid sequence of SEQ ID NO: 2. In yet another preferred embodiment, the nucleic acid molecule is at least 2298 nucleotides in length. In a further preferred embodiment, the nucleic acid molecule is at least 3536 nucleotides in length and encodes a protein having ABCB9 transporter activity (as described herein).
Another embodiment of the invention features nucleic acid molecules, preferably ABCB9 transporter nucleic acid molecules, which specifically detect ABCB9 transporter nucleic acid molecules relative to nucleic acid molecules encoding non-ABCB9 transporter proteins. For example, in one embodiment, such a nucleic acid molecule is at least 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 500-1000, 1000-1500, 1500-2000, or 2000-2500 or more nucleotides in length and/or hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO: 1, or a complement thereof. It should be understood that the nucleic acid molecule can be of a length within a range having one of the numbers listed above as a lower limit and another number as the upper limit for the number of nucleotides in length, e.g., molecules that are 60-80, 300-1000, or 150-400 nucleotides in length.
In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 299-2596 of SEQ ID NO: 1. In other preferred embodiments, the nucleic acid molecules comprise nucleotides 299-2596 of SEQ ID NO: 1.
In other preferred embodiments, the nucleic acid molecule encodes a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule comprising SEQ ID NO: 1 or 3 under stringent conditions.
Another embodiment of the invention provides an isolated nucleic acid molecule which is antisense to an ABCB9 transporter nucleic acid molecule, e.g., the coding strand of an ABCB9 transporter nucleic acid molecule.
Another aspect of the invention provides a vector comprising an ABCB9 transporter nucleic acid molecule. In certain embodiments, the vector is a recombinant expression vector. In another embodiment, the invention provides a host cell containing a vector of the invention. In yet another embodiment, the invention provides a host cell containing a nucleic acid molecule of the invention. The invention also provides a method for producing a protein, preferably an ABCB9 transporter protein, by culturing in a suitable medium, a host cell, e.g., a mammalian host cell such as a non-human mammalian cell, of the invention containing a recombinant expression vector, such that the protein is produced.
Another aspect of this invention features isolated or recombinant ABCB9 transporter proteins and polypeptides. In a preferred embodiment, the protein, preferably an ABCB9 transporter protein, includes at least one transmembrane domain and has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more homologous to the amino acid sequence of SEQ ID NO: 2. In yet another preferred embodiment, the protein, preferably an ABCB9 transporter protein, includes at least one transmembrane domain and is encoded by a nucleic
Connop Bruce P.
Ling Victor
Pollard Michelle L.
Zhang Fang
Active Pass Pharmaceuticals, Inc.
Rao Manjunath
Seed Intellectual Property Law Group PLLC
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