Treatment of decreased bone mineral density with zinc and ring finger 3 (ZNRF3) inhibitors

Patent metadata

Field	Value
Publication number	US-12509687-B2
Application number	US-202318334636-A
Country	US
Kind code	B2
Filing date	Jun 14, 2023
Priority date	Jun 21, 2019
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

The present disclosure provides methods of treating patients having decreased bone mineral density, methods of identifying subjects having increased risk of developing decreased bone mineral density, methods of detecting human Zinc And Ring Finger 3 (ZNRF3) variant nucleic acid molecules and variant polypeptides, and ZNRF3 variant nucleic acid molecules and variant polypeptides.

First claim

What is claimed is:

1 . A method of treating a patient having decreased bone mineral density, the method comprising administering a Zinc And Ring Finger 3 (ZNRF3) inhibitor to the patient, wherein the ZNRF3 inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a ZNRF3 mRNA, wherein the patient is ZNRF3 reference or is heterozygous for a ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide, wherein the human ZNRF3 polypeptide comprises a serine at a position corresponding to position 844 according to SEQ ID NO:18, or a serine at a position corresponding to position 744 according to SEQ ID NO:19.

2 . The method according to claim 1 , wherein the patient has or is suspected of having osteopenia.

3 . The method according to claim 1 , wherein the patient has or is suspected of having osteoporosis.

4 . The method according to claim 1 , wherein the ZNRF3 inhibitor comprises an antisense nucleic acid molecule.

5 . The method according to claim 1 , wherein the ZNRF3 inhibitor comprises an siRNA.

6 . The method according to claim 1 , wherein the human ZNRF3 polypeptide comprises SEQ ID NO:18 or SEQ ID NO:19.

7 . The method according to claim 1 , wherein the ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide comprises a genomic nucleic acid molecule having a nucleotide sequence comprising a deletion of the position corresponding to position 167,122 according to SEQ ID NO:1.

8 . The method according to claim 7 , wherein the ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide comprises a genomic nucleic acid molecule having a nucleotide sequence comprising SEQ ID NO:2.

9 . The method according to claim 1 , wherein the ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide comprises a genomic nucleic acid molecule having a nucleotide sequence comprising a guanine at a position corresponding to position 166,500 according to SEQ ID NO:3.

10 . The method according to claim 1 , wherein the ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide comprises an mRNA molecule having a nucleotide sequence comprising a deletion of the position corresponding to position 2,707 according to SEQ ID NO:4, or a deletion of the position corresponding to position 2,397 according to SEQ ID NO:5.

11 . The method according to claim 10 , wherein the ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide comprises an mRNA molecule having a nucleotide sequence comprising SEQ ID NO:6 or SEQ ID NO: 7.

12 . The method according to claim 1 , wherein the ZNRF3 predicted loss-of-function variant nucleic acid molecule encoding a human ZNRF3 polypeptide comprises an mRNA molecule having a nucleotide sequence comprising a guanine at a position corresponding to position 2,085 according to SEQ ID NO:8, or a guanine at a position corresponding to positions 1,175 according to SEQ ID NO:9.

13 . The method according to claim 12 , wherein the ZNRF3 predicted loss-of-function variant mRNA molecule comprises SEQ ID NO:8 or SEQ ID NO:9.

Assignees

• Regeneron Pharma
• Univ Maryland

Inventors

• Gong Da-Wei
• Gosalia Nehal
• Shuldiner Alan
• Van Hout Cristopher
• Perry James

Classifications

• C12Q1/6874

  involving nucleic acid arrays, e.g. sequencing by hybridisation · CPC title

• A61P19/10

  for osteoporosis · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/20

  involving clustered regularly interspaced short palindromic repeats [CRISPR] · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title