US 12,357,580 B2
Lipid nanoparticle compositions for delivery of mRNA and long nucleic acids
Daniel J. Siegwart, Dallas, TX (US); and Qiang Cheng, Dallas, TX (US)
Assigned to The Board of Regents of The University of Texas System, Austin, TX (US)
Filed by The Board of Regents of The University of Texas System, Austin, TX (US)
Filed on Jun. 14, 2024, as Appl. No. 18/744,370.
Application 18/744,370 is a continuation in part of application No. 18/590,737, filed on Feb. 28, 2024.
Application 18/590,737 is a continuation of application No. 18/534,974, filed on Dec. 11, 2023, granted, now 12,133,924.
Application 18/534,974 is a continuation of application No. 18/529,992, filed on Dec. 5, 2023, abandoned.
Application 18/529,992 is a continuation of application No. 18/186,105, filed on Mar. 17, 2023, abandoned.
Application 18/186,105 is a continuation of application No. 17/929,704, filed on Sep. 4, 2022, granted, now 11,648,210, issued on May 16, 2023.
Application 17/929,704 is a continuation of application No. 17/711,911, filed on Apr. 1, 2022, granted, now 11,510,880, issued on Nov. 29, 2022.
Application 17/711,911 is a continuation of application No. 17/572,615, filed on Jan. 10, 2022, granted, now 11,590,085, issued on Feb. 28, 2023.
Application 17/572,615 is a continuation of application No. 17/473,863, filed on Sep. 13, 2021, granted, now 11,304,911, issued on Apr. 19, 2022.
Application 17/473,863 is a continuation of application No. 17/191,895, filed on Mar. 4, 2021, granted, now 11,229,609, issued on Jan. 25, 2022.
Application 18/744,370 is a continuation in part of application No. 17/124,462, filed on Dec. 16, 2020, abandoned.
Application 17/191,895 is a continuation of application No. PCT/US2019/049565, filed on Sep. 4, 2019.
Application 17/124,462 is a continuation of application No. PCT/US2019/037904, filed on Jun. 19, 2019.
Claims priority of provisional application 62/726,741, filed on Sep. 4, 2018.
Claims priority of provisional application 62/687,010, filed on Jun. 19, 2018.
Prior Publication US 2024/0325315 A1, Oct. 3, 2024
Int. Cl. C07H 21/02 (2006.01); A61K 9/51 (2006.01); A61K 48/00 (2006.01); C12N 9/22 (2006.01); C12N 15/11 (2006.01); C12N 15/113 (2010.01); C12N 15/88 (2006.01)
CPC A61K 9/5123 (2013.01) [A61K 48/0033 (2013.01); C12N 9/22 (2013.01); C12N 15/11 (2013.01); C12N 15/111 (2013.01); C12N 15/113 (2013.01); C12N 15/88 (2013.01); C12N 2310/11 (2013.01); C12N 2310/14 (2013.01); C12N 2310/20 (2017.05); C12N 2320/32 (2013.01)] 26 Claims
 
1. A method for delivering a messenger ribonucleic acid (mRNA) into a cell, the method comprising contacting said cell with a lipid composition encapsulating said mRNA, wherein the lipid composition comprises:
a cationic ionizable lipid at a molar percentage from about 5 to about 30;
a phospholipid at a molar percentage from about 10 to about 45;
a steroid or steroid derivative at a molar percentage from about 15 to about 50; and
a polymer-conjugated lipid at a molar percentage from about 1 to about 6,
wherein the molar percentage is determined based on the total mols of lipids present in the lipid composition;
thereby delivering said mRNA into said cell,
wherein the cationic ionizable lipid is a compound having the structure of Formula (I):
Core-(Repeating Unit)n-Terminating Group  (I),
or a pharmaceutically acceptable salt thereof,
wherein the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a dendron or dendrimer, wherein:
the core is linked to one or more repeating units, wherein:
the core corresponds to the structure of Formula (IV):

OG Complex Work Unit Chemistry
wherein, in Formula (IV):
X3 is selected from —NR6—, —O—, substituted or unsubstituted alkylaminodiyl(C≤8), substituted or unsubstituted alkoxydiyl(C≤8), substituted or unsubstituted arenediyl(C≤8), substituted or unsubstituted heteroarenediyl(C≤8), and substituted or unsubstituted heterocycloalkanediyl(C≤8),
wherein R6 is hydrogen, unsubstituted alkyl(C≤8), or substituted alkyl(C≤8);
R3 and R4 are each independently selected from amino, hydroxy, mercapto, substituted or unsubstituted alkylamino(C≤12), and substituted or unsubstituted dialkylamino(C≤12); and
c and d are each independently 1, 2, 3, 4, 5, or 6;
the repeating unit comprises a degradable diacyl group and optionally a linker; wherein:
the degradable diacyl group has the formula:

OG Complex Work Unit Chemistry
wherein, in Formula (VII):
A1 and A2 are each independently —O— or —NRa—,
wherein Ra is hydrogen or substituted or unsubstituted alkyl(C≤6);
Y3 is selected from substituted or unsubstituted alkanediyl(C≤12), substituted or unsubstituted alkenediyl(C≤12), substituted or unsubstituted arenediyl(C≤12), and a group of the formula:

OG Complex Work Unit Chemistry
wherein:
X3A and X4 are each independently selected from substituted or unsubstituted alkanediyl(C≤12), substituted or unsubstituted alkenediyl(C≤12), and substituted or unsubstituted arenediyl(C≤12); and
Y5 is selected from a covalent bond, substituted or unsubstituted alkanediyl(C≤12), substituted or unsubstituted alkenediyl(C≤12), and substituted or unsubstituted arenediyl(C≤12); and
R9 is substituted or unsubstituted alkyl(C≤8); and
the linker group has the formula:

OG Complex Work Unit Chemistry
wherein, in Formula (VI):
Y1 is selected from substituted or unsubstituted alkanediyl(C≤12), substituted or unsubstituted alkenediyl(C≤12), and substituted or unsubstituted arenediyl(C≤12); and
wherein when the repeating unit comprises a linker group, then the linker group is attached to the degradable diacyl group on both the nitrogen and the sulfur atoms of the linker group, wherein the first group in the repeating unit is the degradable diacyl group, wherein for each linker group, the next group comprises two degradable diacyl groups attached to the nitrogen atom of the linker group; and
wherein n is 1, 2, 3, 4, 5, or 6; and
the terminating group has the formula:

OG Complex Work Unit Chemistry
wherein, in Formula (VIII):
Y4 is unsubstituted alkanediyl(C≤18) or alkanediyl(C≤18) substituted with one or more substituents independently selected from —OH, —F, —Cl, —Br, —I, —SH, —OCH3, —OCH2CH3, —SCH3, and —OC(O)CH3;
R10 is selected from hydrogen, carboxy, hydroxy, aryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), N-heterocycloalkyl(C≤12), —C(O)N(R11)-alkanediyl(C≤6)-heterocycloalkyl(C≤12), —C(O)-alkyl-amino(C≤12), —C(O)-dialkylamino(C≤12), and —C(O)—N-heterocyclo-alkyl(C≤12), wherein:
R11 is hydrogen or substituted or unsubstituted alkyl(C≤6); and
wherein the final degradable diacyl in the chain of repeating unit(s) is attached to the terminating group.