IP Library › Granted Patent US 12,357,675
Granted Patent B2
US 12,357,675 · App. 16/519,607 · Granted Jul 15, 2025

Efficient protein expression in vivo using modified RNA (mod-RNA)

Inventors: Kenneth R. Chien (Cambridge, MA); Leon M. Ptaszek (Newton, MA); Kathy Oi-Lan Lui (Boston, MA); Lior Zangi (Brookline, MA); Wataru Ebina (Boston, MA); Derrick J. Rossi (Roslindale, MA)
A61K38/1866A01K67/0276A61K31/4745A61K31/513A61K31/517A61K31/519A61K31/555A61K31/7068A61K31/7115A61K33/243A61K48/005A61L31/10A61L31/16C12N15/111A01K2207/05A01K2217/075A01K2227/105A01K2267/03A01K2267/0393A61L2300/258C12N2310/11C12N2310/14C12N2800/30
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Quick Facts
Patent No.
US 12,357,675
App. No.
16/519,607
Granted
Jul 15, 2025
Kind
B2
Abstract

Aspects of the invention described herein relate to synthetic, modified RNAs and their use in vivo to modulate gene expression. Aspects of the invention further relate to the use of these synthetic, modified RNAs in myocytes, cardiomyocytes, and tumors.

Claims (15)

1. A method for increasing cardiovascular fate cells in cardiac tissue in a subject with myocardial infarction by expressing a VEGF-A protein in a cardiac tissue in vivo, the method comprising contacting the cardiac tissue in vivo by myocardial injection with a composition comprising a synthetic, modified RNA molecule encoding a VEGF-A 165 polypeptide,

wherein the synthetic, modified RNA molecule comprises at least one or more nucleoside base modifications selected from the group consisting of: pseudouracil, 2 (thio)pseudouracil, 4 (thio)pseudouracil, 2,4-(dithio)psuedouracil, 5-(alkyl)pseudouracil, 5-(methyl)pseudouracil, 5-(alkyl)-2-(thio)pseudouracil, 5-(methyl)-2-(thio)pseudouracil, 5-(alkyl)-4 (thio)pseudouracil, 5-(methyl)-4 (thio)pseudouracil, 5-(alkyl)-2,4 (dithio)pseudouracil, 5-(methyl)-2,4 (dithio)pseudouracil, 1 substituted pseudouracil, 1 substituted 2(thio)-pseudouracil, 1 substituted 4 (thio)pseudouracil, 1 substituted 2,4-(dithio)pseudouracil, 1 (aminocarbonylethylenyl)-pseudouracil, 1 (aminocarbonylethylenyl)-2(thio)-pseudouracil, 1 (aminocarbonylethylenyl)-4 (thio)pseudouracil, 1 (aminocarbonylethylenyl)-2,4-(dithio)pseudouracil, 1 (aminoalkylaminocarbonylethylenyl)-pseudouracil, 1 (aminoalkylamino-carbonylethylenyl)-2(thio)-pseudouracil, 1 (aminoalkylaminocarbonylethylenyl)-4 (thio)pseudouracil, and 1 (aminoalkylaminocarbonylethylenyl)-2,4-(dithio)pseudouracil,

such that introducing said synthetic, modified RNA molecule to a cell in the cardiac tissue in vivo results in increasing cardiovascular fate cells and reduces fibrosis in the cardiac tissue, and also results in a reduced innate immune response relative to a cell in the cardiac tissue in vivo contacted with a synthetic RNA molecule encoding the polypeptide not comprising said modification, wherein the modified RNA molecule encoding a VEGF-A 165 polypeptide promotes WT-1+ epicardial progenitor cells to differentiate into endothelial cells, vascular smooth muscle cells, or cardiomyocytes.

2. The method according to claim 1 , wherein the synthetic, modified RNA molecule further comprises at least one or nucleoside base modification that is 5-methylcytosine.

3. The method of claim 1 , wherein the cardiac tissue is in a subject having a disease or disorder.

4. The method of claim 1 , wherein the cardiac tissue has a reduced capillary density prior to contacting with said composition.

5. The method of claim 1 , wherein said myocardial injection is a single epicardial injection.

6. The method of claim 1 , wherein the subject has experienced an acute ischemic insult to myocardial tissue, and the method reduces the formation of a myocardial infarct.

7. The method of claim 1 , wherein the method promotes recovery of the subject's heart from ischemia.

8. The method of claim 1 , wherein the cardiovascular fate cells are WT-1+ epicardial progenitor cells reprogrammed from a fibroblast-like fate to a myocardial or vascular fate.

9. The method of claim 1 , wherein the WT-1+ epicardial progenitor cells do not develop into fibroblasts or interstitial cells.

10. The method of claim 1 , wherein the modified RNA molecule encoding a VEGF-A 165 polypeptide promotes the generation of islands of de novo cardiomyocytes in the subject's heart.

11. The method of claim 1 , wherein the modified RNA molecule encoding a VEGF-A 165 polypeptide promotes the proliferation of any one or more of endothelial cells, cardiomyocytes, and WT-1+ epicardial cells is stimulated in the subject's heart.

12. The method of claim 1 , wherein the composition is contacted immediately after, or within 1 to 8 weeks after the subject has experienced an acute ischemic insult to myocardial tissue.

13. The method of claim 1 , wherein the cardiovascular fate cells are myocardial fate cells.

Assignments (6)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2019
From: EBINA, WATARU
To: IMMUNE DISEASE INSTITUTE, INC.
Reel/Frame 049888/0653 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2019
From: ROSSI, DERRICK J.
To: IMMUNE DISEASE INSTITUTE, INC.
Reel/Frame 049888/0689 →
MERGER Recorded Jul 29, 2019
From: IMMUNE DISEASE INSTITUTE, INC.
To: THE CHILDREN'S HOSPITAL CORPORATION
Reel/Frame 049888/0698 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2019
From: THE CHILDREN'S HOSPITAL CORPORATION
To: CHILDREN'S MEDICAL CENTER CORPORATION
Reel/Frame 049888/0724 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2019
From: CHIEN, KENNETH R.; PTASZEK, LEON M.; LUI, KATHY OI-LAN
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 049888/0733 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2019
From: ZANGI, LIOR
To: IMMUNE DISEASE INSTITUTE, INC.; THE GENERAL HOSPITAL CORPORATION
Reel/Frame 049893/0840 →
Continuity (5)
Continuation 16015460 · Jun 22, 2018
Continuation 14009351
Provisional Application 61471584 · Apr 4, 2011
Provisional Application 61471166 · Apr 3, 2011
Related Publication 20200000881A1 · Jan 2, 2020
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