Methods of treatment, genetic screening, and disease models for heart conditions associated with RBM20 deficiency

Patent metadata

Field	Value
Publication number	US-12391989-B2
Application number	US-201917289528-A
Country	US
Kind code	B2
Filing date	Oct 25, 2019
Priority date	Oct 30, 2018
Publication date	Aug 19, 2025
Grant date	Aug 19, 2025

Abstract

Methods of treatment, genetic screening, and disease models for heart conditions associated with RBM20 deficiency are disclosed. In particular, methods of treating heart conditions associated with RBM20 deficiency, including RBM20-dependent dilated cardiomyopathy and heart failure with compounds that upregulate expression of RBM20, such as all-trans retinoic acid are provided. Also disclosed are methods of genetic screening to detect the presence of a P633L mutation in RBM20 in order to identify individuals having a genetic predisposition to developing RBM20-dependent DCM. Induced pluripotent stem cell-derived cardiomyocytes (IPSC-CMs) produced by differentiation of IPSCs comprising at least one RBM20 allele encoding a P633L mutation and methods of using them in screening for therapeutics for treating RBM20-dependent DCM are also disclosed.

First claim

What is claimed is:

1. A method of reducing RBM20-mediated splicing defects and increasing cardiomyocyte contractile capacity in a subject who has RBM20-deficient dilated cardiomyopathy (DCM), the method comprising administering an effective amount of all-trans retinoic acid (ATRA) to the subject, wherein the ATRA increases expression of RBM20 in the heart of the subject.

2. The method of claim 1 , wherein the subject is heterozygous or homozygous for a P633L mutation in a RBM20 gene.

3. The method of claim 1 , wherein the subject has deficient RBM20 expression.

4. The method of claim 1 , wherein multiple cycles of treatment are administered to the subject.

5. The method of claim 1 , wherein the ATRA is administered intermittently or according to a daily dosing regimen.

6. The method of claim 1 , wherein the ATRA is administered orally, intravenously, intra-arterially, or intracardially.

7. The method of claim 1 , wherein the ATRA is administered locally to the heart.

8. The method of claim 1 , wherein the subject is human.

9. The method of claim 1 , further comprising administering an angiotensin-converting-enzyme (ACE) inhibitor, a beta blocker, or a diuretic.

10. A method for diagnosing a genetic predisposition to developing RBM20-deficient dilated cardiomyopathy (DCM) and administering all-trans retinoic acid (ATRA) to a subject diagnosed with the genetic predisposition to developing the RBM20-deficient DCM, the method comprising:
a) detecting whether the subject has a P633L mutation in RBM20;
b) diagnosing the subject as having the genetic predisposition to developing RBM-29 dependent the RBM20-deficient DCM when the P633L mutation in the RBM20 is detected; and
c) administering an effective amount of the ATRA to the subject diagnosed as having the genetic predisposition to developing the RBM20-deficient DCM, wherein RBM20-mediated splicing defects are reduced, and cardiomyocyte contractile capacity in the subject is increased.

11. The method of claim 10 , wherein the subject is heterozygous or homozygous for the P633L mutation in the RBM20.

12. The method of claim 10 , further comprising administering a therapeutically effective amount of an angiotensin-converting-enzyme (ACE) inhibitor, a beta blocker, or a diuretic to the subject diagnosed as having the genetic predisposition to developing the RBM20-deficient DCM, or implanting an artificial pacemaker or cardioverter-defibrillator in the subject diagnosed as having the genetic predisposition to developing the RBM20-deficient DCM.

13. The method of claim 10 , wherein said detecting whether the subject has the P633L mutation comprises performing dynamic allele-specific hybridization (DASH), microarray analysis, Tetra-primer ARMS-PCR, a 5′-nuclease allelic discrimination assay; an allelic discrimination assay with Flap endonuclease (FEN), a Serial Invasive Signal Amplification Reaction (SISAR), an oligonucleotide ligase assay, restriction fragment length polymorphism (RFLP), single-strand conformation polymorphism, temperature gradient gel electrophoresis (TGGE), denaturing high performance liquid chromatography (DHPLC), sequencing, or an immunoassay.

14. The method of claim 10 , wherein said detecting whether the subject has the P633L mutation comprises using an allele-specific probe that selectively hybridizes to a nucleic acid comprising an RBM20 gene sequence encoding the P633L mutation or using a set of allele-specific primers capable of selectively amplifying a nucleic acid comprising an RBM20 gene sequence encoding the P633L mutation.

15. The method of claim 10 , further comprising detecting whether one or more other mutations in the RBM20 are present in at least one allele of an RMB20 gene in the subject's genome, wherein the one or more other mutations in the RBM20 are selected from the group consisting of R634Q, R634W, S635A, R636S, R636H, R636C, S637G, P638L, E913K, V535I, and R716Q, wherein said diagnosing the subject as having the genetic predisposition to developing the RBM20-deficient DCM comprises detecting the P633L mutation in the RBM20 in combination with the one or more other mutations in the RBM20 selected from the group consisting of R634Q, R634W, S635A, R636S, R636H, R636C, S637G, P638L, E913K, V535I, and R716Q.

Assignees

• Univ Leland Stanford Junior
• European Molecular Biology Laboratory

Inventors

• Briganti Francesca
• Steinmetz Lars M
• Sun Han
• Wei Wu

Classifications

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• A61K31/203

  Retinoic acids {; Salts thereof} · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C12Q1/6883 Primary

  for diseases caused by alterations of genetic material · CPC title