Methods for detecting the presence of or predisposition to autosomal dominant hypercholesterolemia

• US 7,300,754 B2
• Filed: 04/23/2004
• Issued: 11/27/2007
• Est. Priority Date: 04/25/2003
• Status: Expired due to Fees

• Current Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Original Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Inventors: Boileau, Catherine, Seidah, Nabil G., Varret, Mathilde, Abi Fadel, Marianne, Rabes, Jean-Pierre
• Primary Examiner(s): MYERS, CARLA J
• Application Number:
  US10/830,454
• Publication Number:
  US 20040248177A1
• Time in Patent Office: 1,313 Days
• Field of Search: None
• 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: C12N 9/6424 Serine endopeptidases (3.4.21)
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The present invention discloses the identification of a human hypercholesterolemia causal gene, which can be used for the diagnosis, prevention and treatment of hypercholesterolemia, more particularly familial hypercholesterolemia, as well as for the screening of therapeutically active drugs. The invention more specifically disclosed that mutations in the PCSK9 gene encoding NARC-1 causes autosomal dominant hypercholesterolemia and represent novel targets for therapeutic intervention. The invention can be used in the diagnosis of predisposition to, detection, prevention and/or treatment of coronary heart disease and, cholesterol, lipid and lipoprotein metabolism disorders, including familial hypercholesterolemia, atherogenic dyslipidemia, atherosclerosis, cardiovascular diseases.

Claims

1. A method of detecting the presence of or predisposition to autosomal dominant hypercholesterolemia in a human subject, the method comprising (i) providing a nucleic acid sample comprising a PCSK9 nucleic acid sequence from the subject and (ii) detecting the presence of an alteration in the PCSK9 nucleic acid sequence, the alteration being a T→

A or T→

G substitution at nucleotide 625 of SEQ ID NO;

1, said alteration in said nucleic acid sequence being indicative of the presence of or predisposition to autosomal dominant hypercholesterolemia.

2. The method according to claim 1, wherein said alteration leads to a decrease in expression of the N2 form of NARC-1 encoded by the PCSK9 nucleic acid sequence.

3. The method according to claim 1, wherein said alteration is a T→

A substitution at nucleotide 625 of SEQ ID NO;

1.

4. The method according to claim 2, wherein said alteration in the nucleic acid is one which encodes for an amino acid substitution of a Serine at position 127.

5. The method according to claim 2, wherein said alteration in the nucleic acid is one which encodes for an amino acid substitution of a Serine at position 127 by an Arginine.