SIRNA-based therapy of Fibrodyplasia Ossificans Progressiva (FOP)

• US 8,859,752 B2
• Filed: 10/17/2012
• Issued: 10/14/2014
• Est. Priority Date: 04/18/2006
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Shore, Eileen M., Kaplan, Frederick S.
• Primary Examiner(s): Angell, Jon E
• Application Number:
  US13/654,208
• Publication Number:
  US 20130041017A1
• Time in Patent Office: 727 Days
• Field of Search: 536/24.5, 514/44.A
• US Class Current: 536/24.5
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/34 Allele or polymorphism specific uses
• 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

This invention is directed to mutated Activin A type I receptor proteins (ACVR1) and isolated nucleic acids encoding same. The invention also relates to compositions and methods for siRNA-based regulation of mutated ACVR1 expression in the treatment of Fibrodysplasia Ossificans Progressiva (FOP).

Claims

1. A method of treating Fibrodysplasia Ossificans Progressiva (FOP) in a subject, comprising the step of administering to said subject a therapeutically effective amount of a siRNA specific against a nucleic acid encoding a mutated Activin A type I receptor (ACVR1) represented by SEQ ID NO:

21 relative to a nucleic acid encoding wild-type Activin A type I receptor protein (ACVR1) as set forth in SEQ ID NO;

26, wherein said siRNA has a passenger strand selected from SEQ ID NO;

56 or SEQ ID NO;

57.

2. The method of claim 1, whereby treating comprises inhibiting, delaying onset or preventing.

3. The method of claim 1, whereby treating comprises reducing the incidence of, alleviating symptoms or both.

4. The method of claim 1, whereby the Fibrodysplasia Ossificans Progressiva (FOP) is inherited Fibrodysplasia Ossificans Progressiva (FOP).

5. The method of claim 1, whereby the Fibrodysplasia Ossificans Progressiva (FOP) is sporadic Fibrodysplasia Ossificans Progressiva (FOP).

6. A method of treating a pathology associated with heterotopic ossification in a subject, comprising the step of administering to said subject a therapeutically effective amount of a siRNA specific against a nucleic acid encoding a mutated Activin A type I receptor (ACVR1) represented by SEQ ID NO:

21 relative to a nucleic acid encoding wild-type Activin A type I receptor protein (ACVR1) as set forth in SEQ ID NO;

26, wherein said siRNA has a passenger strand selected from SEQ ID NO;

56 or SEQ ID NO;

57.

7. The method of claim 6, whereby the pathology associated with heterotopic ossification is hip replacement surgery, valvular heart disease, closed head trauma, spinal cord injuries, sports injuries, blast injuries, or a combination thereof.

8. The method of claim 7, further comprising administering to said subject a therapeutically effective amount of a BMP signal-transduction inhibitor.

9. An allele-specific siRNA, comprising a siRNA specific against a nucleic acid encoding a mutated Activin A type I receptor (ACVR1) represented by SEQ ID NO:

21 relative to a nucleic acid encoding wild-type Activin A type I receptor protein (ACVR1) as set forth in SEQ ID NO;

26 wherein said siRNA has a passenger strand selected from SEQ ID NO;

56 or SEQ ID NO;

57.