Nucleic acids encoding microsomal trigyceride transfer protein

• US 5,595,872 A
• Filed: 09/03/1993
• Issued: 01/21/1997
• Est. Priority Date: 03/06/1992
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Dickson, John K., Sharp, Daru Y., Lawrence, R. Michael, Gregg, Richard E., Lawson, John E., Biller, Scott A., Holava, Henry M., Wetterau, John R. II, Partyka, Richard A.
• Primary Examiner(s): Zitomer, Stephanie W.
• Application Number:
  US08/117,362
• Time in Patent Office: 1,236 Days
• Field of Search: 435/6, 435/240.2, 435/320.1, 536/23.5
• US Class Current: 435/6.11
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 295/112 with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 14/47 : from mammals
• CPC Class Codes: G01N 2800/044 : Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
• CPC Class Codes: G01N 33/92 : involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

Nucleic acid sequences, particularly DNA sequences, coding for all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, expression vectors containing the DNA sequences, host cells containing the expression vectors, and methods utilizing these materials. The invention also concerns polypeptide molecules comprising all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, and methods for producing these polypeptide molecules. The invention additionally concerns novel methods for preventing, stabilizing or causing regression of atherosclerosis and therapeutic agents having such activity. The invention concerns further novel methods for lowering serum liquid levels and therapeutic agents having such activity.

Claims

1. An isolated nucleic acid molecule consisting of an MTP nucleotide sequence, wherein the MTP nucleotide sequence encodes the high molecular weight subunit of microsomal triglyceride transfer protein.

2. The nucleic acid molecule according to claim 1 which is a DNA molecule.

3. The DNA molecule according to claim 2 consisting of all or part of the MTP nucleotide sequence, wherein said all or part is selected from SEQ. ID. NOS. 1, 2, 5, 7, 8, 1 together with 5, 2 together with 7, the first 108 bases of 2 together with 8, the first 108 bases of 2 together with 7 and 8, and 8 together with SEQ. ID, NOS. 31 and 32.

4. A DNA molecule having a nucleotide sequence fully complementary to the MTP nucleotide sequence of claim 1.

5. A DNA molecule having a nucleotide sequence fully complementary to the selected all or part of MTP nucleotide sequence of claim 3.

6. An expression vector comprising an MTP nucleotide sequence, wherein the MTP nucleotide sequence encodes the high molecular weight subunit of microsomal triglyceride transfer protein.

7. The expression vector according to claim 6 wherein the MTP nucleotide sequence is all or part of the MTP nucleotide sequence selected from SEQ. ID. NOS. 1, 2, 5, 7, 8, 1 together with 5, 2 together with 7, the first 108 bases of 2 together with 8, the first 108 bases of 2 together with 7 and 8, and 8 together with SEQ. ID. NOS. 31 and 32.

8. A prokaryotic or eukaryotic host cell comprising the expression vector according to claim 6.

9. A prokaryotic or eukaryotic host cell comprising the expression vector according to claim 7.

10. A method for detecting a nucleic acid having an MTP nucleotide sequence, which comprises:

(a) contacting said nucleic acid with a detectable marker consisting of a labeled nucleic acid sequence which binds specifically to at least part of the nucleic acid having an MTP nucleotide sequence, and

(b) detecting the marker so bound;

wherein the presence of bound marker indicates the presence of the nucleic acid having an MTP nucleotide sequence, and wherein the MTP nucleotide sequence encodes the high molecular weight subunit of microsomal triglyceride transfer protein.

11. The method according to claim 10 wherein the detectable marker consists of a nucleotide sequence of 15 to 33 sequential nucleotides of SEQ. ID. NOS. 1, 2, 5, 7, 8, 1 together with 5, 2 together with 7, the first 108 bases of 2 together with 8, the first 108 bases of 2 together with 7 and 8, or 8 together with SEQ. ID. NOS. 31 and 32.

12. The method according to claim 10 wherein the detectable marker consists of a nucleotide sequence of 15 to 33 sequential nucleotides fully complementary to a nucleotide sequence selected from SEQ. ID. NOS. 1, 2, 5, 7, 8, 1 together with 5, 2 together with 7, the first 108 bases of 2 together with 8, the first 108 bases of 2 together with 7 and 8, and 8 together with SEQ. ID. NOS. 31 and 32.

13. The method according to claim 10 wherein the nucleic acid having an MTP nucleotide sequence is selected from the group consisting of genomic DNA, cDNA, and RNA.

14. The method according to claim 10 wherein the detectable marker is labeled with a radioisotope and the detecting step is carried out by autoradiography.