IP Library › Granted Patent US 12,257,318
Granted Patent B2
US 12,257,318 · App. 18/431,504 · Granted Mar 25, 2025

Polynucleotide compositions, related formulations, and methods of use thereof

Inventors: Mirko Hennig (Mountain View, CA); Daniella Ishimaru (Menlo Park, CA); David J. Lockhart (Menlo Park, CA); Michael Torres (Menlo Park, CA); Jackson Eby (Menlo Park, CA); Dmitri Boudko (Menlo Park, CA); Brandon A. Wustman (San Diego, CA)
Assignee: ReCode Therapeutics, Inc.
A61K48/005A61K9/0078A61K9/12A61K9/1271A61K9/5123A61K38/1709A61K48/0075
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Quick Facts
Patent No.
US 12,257,318
App. No.
18/431,504
Granted
Mar 25, 2025
Kind
B2
Abstract

Compositions of polynucleotide(s), pharmaceutical compositions thereof, and methods of use thereof are disclosed. A polynucleotide may encode for a cystic fibrosis transmembrane conductance regulator (CFTR) protein or a functional fragment thereof. The polynucleotide may be assembled with a lipid composition for targeted delivery to a cell or an organ, such as a lung cell or a lung of a subject. Methods for enhancing an expression or activity of CFTR protein in a cell are provided. Methods for treating a subject having or suspected of having a CFTR-associated condition are also provided.

Claims (84)

1. A pharmaceutical composition comprising a synthetic polynucleotide assembled with a lipid composition,

wherein said synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein that comprises a nucleic acid sequence having at least about 98% sequence identity to SEQ ID NO: 4,

wherein said lipid composition comprises

an ionizable cationic lipid at a molar percentage of about 5% to about 30%;

a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid at a molar percentage of about 5% to about 30%;

a phospholipid at a molar percentage of about 5% to about 25%;

a steroid or steroid derivative at a molar percentage of about 15% to about 46%; and

a polymer-conjugated lipid at a molar percentage of about 0.5% to about 10%.

2. The pharmaceutical composition of claim 1 , wherein said synthetic polynucleotide is a messenger ribonucleic acid (mRNA).

3. The pharmaceutical composition of claim 1 , wherein said synthetic polynucleotide comprises 1-methylpseudouridine.

4. The pharmaceutical composition of claim 1 , wherein said synthetic polynucleotide further comprises a 3′- or 5′-noncoding region.

5. The pharmaceutical composition of claim 4 , wherein said synthetic polynucleotide further comprises a 5′ cap structure.

6. The pharmaceutical composition of claim 5 , wherein the 5′ cap structure comprises a nucleic acid sequence having at least about 90% sequence identity to SEQ ID NO: 6.

7. The pharmaceutical composition of claim 5 , wherein the 5′ cap structure comprises a nucleic acid sequence according to SEQ ID NO: 6.

8. The pharmaceutical composition of claim 4 , wherein said 3′-noncoding region comprises a poly adenosine tail.

9. The pharmaceutical composition of claim 8 , wherein said poly adenosine tail comprises at most 200 adenosines.

10. The pharmaceutical composition of claim 4 , wherein said 3′- or 5′-noncoding region enhances an expression or activity of said CFTR protein encoded by said synthetic polynucleotide within a cell.

11. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition is an aerosol composition.

12. The pharmaceutical composition of claim 11 , wherein the droplet size of the aerosol droplets in said aerosol composition is from 0.5 μm to 10 μm.

13. The pharmaceutical composition of claim 11 , wherein the median droplet size of the aerosol droplets in said aerosol composition is from 0.5 μm to 10 μm.

14. The pharmaceutical composition of claim 11 , wherein the average droplet size of the aerosol droplets in said aerosol composition is from 0.5 μm to 10 μm.

15. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition is formulated for apical delivery.

16. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition is formulated for nebulization.

17. The pharmaceutical composition of claim 1 , wherein said lipid composition comprises

an ionizable cationic lipid at a molar percentage of about 10% to about 25%;

a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid at a molar percentage of about 10% to about 30%;

a phospholipid at a molar percentage of about 5% to about 25%;

a steroid or steroid derivative at a molar percentage of about 15% to about 46%; and

a polymer-conjugated lipid at a molar percentage of about 3% to about 5%.

18. The pharmaceutical composition of claim 17 , wherein the polymer-conjugated lipid comprises a poly(ethylene glycol) (PEG)-conjugated lipid.

19. The pharmaceutical composition of claim 17 , wherein the polymer-conjugated lipid is 1,2-dimyristoyl-sn-glycero-methoxypolyethylene glycol.

20. The pharmaceutical composition of claim 1 , wherein said lipid composition comprises

4A3-SC7 at a molar percentage of about 10% to about 25%;

1,2-Dioleoyl-3-dimethylammonium-propane (DODAP) at a molar percentage of about 10% to about 30%;

dioleoylphosphatidylethanolamine (DOPE) at a molar percentage of about 5% to about 25%;

cholesterol at a molar percentage of about 15% to about 46%; and

DMG-PEG at a molar percentage of about 3% to about 5%.

21. The pharmaceutical composition of claim 1 , wherein said lipid composition comprises

4A3-SC7 at a molar percentage of about 15%;

1,2-Dioleoyl-3-dimethylammonium-propane (DODAP) at a molar percentage of about 16%;

dioleoylphosphatidylethanolamine (DOPE) at a molar percentage of about 22%;

cholesterol at a molar percentage of about 44%; and

DMG-PEG at a molar percentage of about 3%.

22. The pharmaceutical composition of claim 1 ,

wherein said synthetic polynucleotide comprises a nucleic acid sequence having at least about 98% sequence identity to SEQ ID NO: 4, and

wherein said lipid composition comprises

4A3-SC7 at a molar percentage of about 15%;

1,2-Dioleoyl-3-dimethylammonium-propane (DODAP) at a molar percentage of about 16%;

dioleoylphosphatidylethanolamine (DOPE) at a molar percentage of about 22%;

cholesterol at a molar percentage of about 44%; and

DMG-PEG at a molar percentage of about 3%.

23. The pharmaceutical composition of claim 1 ,

wherein said synthetic polynucleotide comprises a nucleic acid sequence according to SEQ ID NO: 4, and

wherein said lipid composition comprises

4A3-SC7 at a molar percentage of about 15%;

1,2-Dioleoyl-3-dimethylammonium-propane (DODAP) at a molar percentage of about 16%;

dioleoylphosphatidylethanolamine (DOPE) at a molar percentage of about 22%;

cholesterol at a molar percentage of about 44%; and

DMG-PEG at a molar percentage of about 3%.

24. The pharmaceutical composition of claim 1 , wherein the polymer-conjugated lipid comprises a poly(ethylene glycol) (PEG)-conjugated lipid.

25. The pharmaceutical composition of claim 1 , wherein the polymer-conjugated lipid is a 1,2-dimyristoyl-sn-glycero-methoxypolyethylene glycol.

26. The pharmaceutical composition of claim 1 , wherein the ionizable cationic lipid is a compound having the structural formula:

Core-Repeating Unit-Terminating Group (D-I),

or a pharmaceutically acceptable salt thereof, wherein:

the core is linked to two to six repeating units by removing two to six hydrogen atoms from the core and replacing the hydrogen atoms with the repeating units; wherein:

the core has the formula:

wherein, in Formula (D-IV):

X 3 is —NR 6 —, —O—, or optionally substituted alkylaminodiyl (c≤8) ; wherein R 6 is hydrogen, alkyl (c≤8) , or substituted alkyl (c≤8) ,

R 3 and R 4 are each independently amino, optionally substituted alkylamino (c≤12) , or optionally substituted dialkylamino (c≤12) ;

wherein:

c and d are each independently 1, 2, 3, 4, 5, or 6;

the repeating unit comprises a degradable diacyl group of the formula:

wherein, in Formula (D-VII):

A 1 and A 2 are each independently —O—;

Y 3 is —CH 2 CH 2 —; and

R 9 is —CH 3 ; and

the terminating group has the formula:

wherein, in Formula (D-VIII):

Y 4 is alkanediyl (c≤18) or an alkanediyl (c≤18) ; and

R 10 is hydrogen.

27. The pharmaceutical composition of claim 1 , wherein the ionizable cationic lipid is:

28. The pharmaceutical composition of claim 1 , wherein the SORT lipid is 1,2-Dioleoyl-3-dimethylammonium-propane (DODAP).

29. The pharmaceutical composition of claim 1 , wherein the SORT lipid is selected from 1,2-dimyristoyl-3-trimethylammonium-propane (14:0 TAP), 1,2-dipalmitoyl-3-trimethylammonium-propane (16:0 TAP), 1,2-stearoyl-3-trimethylammonium-propane (18:0 TAP), and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP).

30. The pharmaceutical composition of claim 1 , wherein the SORT lipid is selected from 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine (12:0 EPC), 1,2-Dioleoyl-sn-glycero-3-ethylphosphocholine (14:0 EPC), 1,2-dimyristoleoyl-sn-glycero-3-ethylphosphocholine (14:1 EPC), 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (16:0 EPC), 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (18:0 EPC), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (18:1 EPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (16:0-18:1 EPC).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 23, 2024
From: HENNIG, MIRKO; ISHIMARU, DANIELLA; LOCKHART, DAVID J.; TORRES, MICHAEL; EBY, JACKSON; BOUDKO, DMITRI; WUSTMAN, BRANDON
To: RECODE THERAPEUTICS, INC.
Reel/Frame 067508/0248 →
Continuity (5)
Continuation 18283523
Provisional Application 63274912 · Nov 2, 2021
Provisional Application 63208966 · Jun 9, 2021
Provisional Application 63164573 · Mar 23, 2021
Related Publication 20240269325A1 · Aug 15, 2024
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