IP Library › Granted Patent US 12,533,402
Granted Patent B2
US 12,533,402 · App. 17/543,543 · Granted Jan 27, 2026

MRNA therapy for argininosuccinate synthetase deficiency

Inventors: Michael Heartlein (Lexington, MA); Frank DeRosa (Lexington, MA); Lianne Boeglin (Lexington, MA)
Assignee: TRANSLATE BIO, INC.
A61K38/53A61K9/1272A61K9/5123A61K31/7105C12N9/93C12Y603/04005A61K48/00A61K48/005
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Quick Facts
Patent No.
US 12,533,402
App. No.
17/543,543
Granted
Jan 27, 2026
Kind
B2
Abstract

The present invention provides, among other things, methods of treating Argininosuccinate Synthetase Deficiency (ASD), including administering to a subject in need of treatment a composition comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose and an administration interval such that at least one symptom or feature of ASD is reduced in intensity, severity, or frequency or has delayed in onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.

Claims (32)

1 . A composition for treating Argininosuccinate Synthetase Deficiency (ASD), comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose encapsulated within a liposome, wherein the mRNA encodes an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:2, wherein the mRNA further comprises a 5′ untranslated region (UTR), wherein the 5′ UTR comprises the nucleic acid sequence of SEQ ID NO:4, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more poly(ethylene) (PEG)-modified lipids.

2 . The composition of claim 1 , wherein the one or more cationic lipids constitute about 40% of the liposome by molar ratio.

3 . The composition of claim 1 , wherein the one or more cationic lipids constitute about 30-50% of the liposome by molar ratio.

4 . The composition of claim 1 , wherein the one or more PEG-modified lipids comprise a PEG chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C 6 -C 20 length.

5 . The composition of claim 1 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:30:25:5 by molar ratio.

6 . The composition of claim 1 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:32:25:3 by molar ratio.

7 . The composition of claim 1 , wherein the liposome has a size less than about 100 nm.

8 . A composition for treating ASD, comprising an mRNA encoding ASS1 at an effective dose encapsulated within a liposome, wherein the mRNA encodes an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:2, wherein the mRNA further comprises a 3′ UTR, wherein the 3′ UTR comprises the nucleic acid sequence of SEQ ID NO:5, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

9 . The composition of claim 8 , wherein the one or more cationic lipids constitute about 40% of the liposome by molar ratio.

10 . The composition of claim 8 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:30:25:5 by molar ratio.

11 . The composition of claim 8 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:32:25:3 by molar ratio.

12 . The composition of claim 8 , wherein the one or more cationic lipids constitute about 30-50% of the liposome by molar ratio.

13 . A composition for treating ASD, comprising an mRNA encoding ASS1 at an effective dose encapsulated within a liposome, wherein the mRNA comprises a nucleic acid sequence that is at least 90% identical to the nucleic acid sequence of SEQ ID NO: 13, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

14 . The composition of claim 13 , wherein the one or more cationic lipids constitute about 40% of the liposome by molar ratio.

15 . The composition of claim 13 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:30:25:5 by molar ratio.

16 . The composition of claim 13 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:32:25:3 by molar ratio.

17 . The composition of claim 13 , wherein the one or more cationic lipids constitute about 30-50% of the liposome by molar ratio.

18 . A composition for treating ASD, comprising an mRNA encoding ASS1 at an effective dose encapsulated within a liposome, wherein the mRNA encodes an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:2, wherein the mRNA further comprises a 3′ UTR, wherein the 3′ UTR comprises the nucleic acid sequence of SEQ ID NO:6, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

19 . The composition of claim 18 , wherein the one or more cationic lipids constitute about 40% of the liposome by molar ratio.

20 . The composition of claim 18 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:30:25:5 by molar ratio.

21 . The composition of claim 18 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:32:25:3 by molar ratio.

22 . The composition of claim 18 , wherein the one or more cationic lipids constitute about 30-50% of the liposome by molar ratio.

23 . A composition for treating ASD, comprising an mRNA encoding ASS1 at an effective dose encapsulated within a liposome, wherein the mRNA comprises a nucleic acid sequence that is at least 90% identical to the nucleic acid sequence of SEQ ID NO: 14, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

24 . The composition of claim 23 , wherein the one or more cationic lipids constitute about 40% of the liposome by molar ratio.

25 . The composition of claim 23 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:30:25:5 by molar ratio.

26 . The composition of claim 23 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:32:25:3 by molar ratio.

27 . The composition of claim 23 , wherein the one or more cationic lipids constitute about 30-50% of the liposome by molar ratio.

28 . A composition for treating ASD, comprising an mRNA encoding ASS1 at an effective dose encapsulated within a liposome, wherein the mRNA comprises a nucleic acid sequence that is at least 90% identical to the nucleic acid sequence of SEQ ID NO: 15, and wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

29 . The composition of claim 28 , wherein the one or more cationic lipids constitute about 40% of the liposome by molar ratio.

30 . The composition of claim 28 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:30:25:5 by molar ratio.

31 . The composition of claim 28 , wherein the ratio of cationic lipid:non-cationic lipid:cholesterol-based lipid:PEG-modified lipid is approximately 40:32:25:3 by molar ratio.

32 . The composition of claim 28 , wherein the one or more cationic lipids constitute about 30-50% of the liposome by molar ratio.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2022
From: HEARTLEIN, MICHAEL; DEROSA, FRANK; BOEGLIN, NEE SMITH, LIANNE
To: SHIRE HUMAN GENETIC THERAPIES, INC.
Reel/Frame 060349/0041 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2022
From: HEARTLEIN, MICHAEL; DEROSA, FRANK; SMITH, LIANNE
To: SHIRE HUMAN GENETIC THERAPIES, INC.
Reel/Frame 059271/0677 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2022
From: SHIRE HUMAN GENETIC THERAPIES, INC.
To: RANA THERAPEUTICS, INC.
Reel/Frame 059367/0571 →
CHANGE OF NAME Recorded Mar 15, 2022
From: RANA THERAPEUTICS, INC.
To: TRANSLATE BIO, INC.
Reel/Frame 059367/0641 →
Continuity (3)
Division 14521351 · Oct 22, 2014
Provisional Application 61894294 · Oct 22, 2013
Related Publication 20220218803A1 · Jul 14, 2022
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