US 2024/0189449 A1Published application

Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency

AssigneeModernaTX, Inc.

InventorsKerry Benenato, Alicia Anne Bicknell, Mark Cornebise, Athanasios Dousis, Andrew Jacob Giessel, Edward Hennessy, Ruchi Jain, Caroline Köhrer, Stuart Spencer Licht, Kanchana Ravichandran, David Reid

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Abstract

This disclosure relates to mRNA therapy for the treatment of ornithine transcarbamylase deficiency (OTCD). mRNAs for use in the invention, when administered in vivo, encode human ornithine transcarbamylase (OTC). mRNA therapies of the disclosure increase and/or restore deficient levels of OTC expression and/or activity in subjects. mRNA therapies of the disclosure further decrease levels of toxic ammonia associated with deficient OTC activity in subjects.

Claims93

Dependent claims

A lipid nanoparticle comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding an ornithine transcarbamylase (OTC) polypeptide, wherein the lipid nanoparticle comprises a compound of Formula (II):

or its N-oxide, or a salt or isomer thereof,
wherein R′a is R′branched or R′cyclic;
wherein
R′branched is:
and R′cyclic is:
and
R′b is:
wherein
denotes a point of attachment;
Raγ and Raδ are each independently selected from the group consisting of H, C1-12 alkyl, and C2-12 alkenyl, wherein at least one of Raγ and Raδ as is selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
Rbγ and Rbδ are each independently selected from the group consisting of H, C1-12 alkyl, and C2-12 alkenyl, wherein at least one of Rbγ and Rbδ is selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
R2 and R3 are each independently selected from the group consisting of C1-14 alkyl and
C2-14 alkenyl;
R4 is selected from the group consisting of —(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and
wherein
denotes a point of attachment;
wherein
R10 is N(R)2;
each R is independently selected from the group consisting of C1-6 alkyl, C2-3 alkenyl, and H;
and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
each R′ independently is a C1-12 alkyl or C2-12 alkenyl;
Ya is a C3-6 carbocycle;
R*″a is selected from the group consisting of C1-15 alkyl and C2-15 alkenyl;
and
s is 2 or 3;
m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9.

24 more elements

or its N-oxide, or a salt or isomer thereof,
wherein R′a is R′branched, wherein
R′branched is:
wherein
denotes a point of attachment;
wherein Raα, Raβ, Raγ, and Raδ are each independently selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl;
R2 and R3 are each independently selected from the group consisting of C1-14 alkyl and
C2-14 alkenyl;
R4 is
wherein
denotes a point of attachment;
wherein
R10 is N(R)2;
each R is independently selected from the group consisting of C1-6 alkyl, C2-3 alkenyl, and H;
n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
each R5 is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
each R6 is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
M and M′ are each independently selected from the group consisting of —C(O)O— and
—OC(O)—;
R′ is a C1-12 alkyl or C2-12 alkenyl;
l is selected from the group consisting of 1, 2, 3, 4, and 5;
and
m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/282,647Filed 24 Mar 2022
Priority: 24 Mar 2021
Published: 13 Jun 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

A61K 48/005
Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy:…
A61K 9/1271
Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant: non-conventional liposomes,…
A61K 9/1272
Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers: comprising non-phosphatidyl surfactants as…
A61K 9/5123
Excipients; Inactive ingredients: organic compounds, e.g. fats, sugars

Family

Application63/165,692Us provisional application · filed 24 Mar 2021
US 2024/0189449 A1This patent

From the US filing history. Foreign family members aren’t listed.

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