Compounds and compositions for intracellular delivery of therapeutic agents
AssigneeModernaTX, Inc.
InventorsKerry E. BENENATO, Mark CORNEBISE, Edward HENNESSY
Life of this patent
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Abstract
The disclosure features novel lipids and compositions involving the same. Nanoparticle compositions include a novel lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Nanoparticle compositions further including therapeutic and/or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.
Claims87
A compound of Formula (I):
- or its N-oxide,
- or a salt or isomer thereof, wherein:
- R1 is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;
- R2 and R3 are independently selected from the group consisting of H, C1-14 alkyl, C2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R2 and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;
- R4 is selected from the group consisting of —(CH2)nQ, —(CH2)nCHQR, —(CH2)oC(R12)2(CH2)n-oQ, —CHQR, —CQ(R)2, and —C(O)NQR, where Q is —(CH2)nN(R)2, each o is independently selected from 1, 2, 3, and 4, and each n is independently selected from 1, 2, 3, 4, and 5;
- each R5 is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;
- each R6 is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;
- M and M′ are independently selected from —C(O)O—, —OC(O)—, —OC(O)-M″—C(O)O—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group, in which M″ is a bond, C1-13 alkyl or C2-13 alkenyl;
- R7 is selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
- R12 is selected from the group consisting of H, OH, C1-3 alkyl, and C2-3 alkenyl;
- each R is independently selected from the group consisting of C1-6 alkyl, C1-3 alkyl-aryl, C2-3 alkenyl, and H;
- each R′ is independently selected from the group consisting of C1-18 alkyl, C2-18 alkenyl, —R*YR″, —YR″, (CH2)qOR*, and H,
- and each q is independently selected from 1, 2, and 3;
- each R″ is independently selected from the group consisting of C3-15 alkyl and C3-15 alkenyl;
- each R* is independently selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
- each Y is independently a C3-6 carbocycle;
- each X is independently selected from the group consisting of F, Cl, Br, and I;
- and
- m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.
A compound of Formula (I):
- or its N-oxide,
- or a salt or isomer thereof, wherein:
- or a salt or isomer thereof, wherein
- R1 is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, —R*YR″, —YR″, and —R″M′ R′;
- R2 and R3 are independently selected from the group consisting of H, C1-14 alkyl, C2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R2 and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;
- R4 is selected from the group consisting of —(CH2)nQ, —(CH2)nCHQR, —(CH2)oC(R12)2(CH2)n-oQ, —CHQR, —CQ(R)2, and —C(O)NQR, where Q is —(CH2)nN(R)2, each o is independently selected from 1, 2, 3, and 4, and each n is independently selected from 1, 2, 3, 4, and 5;
- Rx is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, —(CH2)rOH, and —(CH2)rNR2,
- wherein r is selected from 1, 2, 3, 4, 5, and 6;
- each R5 is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;
- each R6 is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;
- M and M′ are independently selected from —C(O)O—, —OC(O)—, —OC(O)-M″—C(O)O—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group, in which M″ is a bond, C1-13 alkyl or C2-13 alkenyl;
- R7 is selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
- R8 is selected from the group consisting of C3-6 carbocycle and heterocycle;
- R9 is selected from the group consisting of H, CN, NO2, C1-6 alkyl, —OR, —S(O)2R, —S(O)2N(R)2, C2-6 alkenyl, C3-6 carbocycle and heterocycle;
- R12 is selected from the group consisting of H, OH, C1-3 alkyl, and C2-3 alkenyl;
- each R is independently selected from the group consisting of C1-6 alkyl, C1-3 alkyl-aryl, C2-3 alkenyl, (CH2)qOR*, and H,
- and each q is independently selected from 1, 2, and 3;
- each R′ is independently selected from the group consisting of C1-18 alkyl, C2-18 alkenyl, —R*YR″, —YR″, and H;
- each R″ is independently selected from the group consisting of C3-15 alkyl and C3-15 alkenyl;
- each R* is independently selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
- each Y is independently a C3-6 carbocycle;
- each X is independently selected from the group consisting of F, Cl, Br, and I;
- and
- m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.
A compound of Formula (VI):
- or its N-oxide,
- or a salt or isomer thereof, wherein
- R1 is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;
- R2 and R3 are independently selected from the group consisting of H, C1-14 alkyl, C2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R2 and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;
- each R5 is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;
- each R6 is independently selected from the group consisting of OH, C1-3 alkyl, C2-3 alkenyl, and H;
- M and M′ are independently selected from —C(O)O—, —OC(O)—, —OC(O)-M″—C(O)O—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group, in which M″ is a bond, C1-13 alkyl or C2-13 alkenyl;
- R7 is selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H;
- each R is independently selected from the group consisting of H, C1-3 alkyl, and C2-3 alkenyl;
- RN is H, or C1-3 alkyl;
- each R′ is independently selected from the group consisting of C1-18 alkyl, C2-18 alkenyl, —R*YR″, —YR″, and H;
- each R″ is independently selected from the group consisting of C3-15 alkyl and C3-15 alkenyl;
- each R* is independently selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
- each Y is independently a C3-6 carbocycle;
- each X is independently selected from the group consisting of F, Cl, Br, and I;
- Xa and Xb are each independently O or S;
- R10 is selected from the group consisting of H, halo, —OH, R, —N(R)2, —CN, —N3, —C(O)OH, —C(O)OR, —OC(O)R, —OR, —SR, —S(O)R, —S(O)OR, —S(O)2OR, —NO2, —S(O)2N(R)2, —N(R)S(O)2R, —NH(CH2)t1N(R)2, —NH(CH2)p1O(CH2)q1N(R)2, —NH(CH2)s1OR, —N((CH2)sOR)2, —N(R)-carbocycle, —N(R)-heterocycle, —N(R)-aryl, —N(R)-heteroaryl, —N(R)(CH2)t1-carbocycle, —N(R)(CH2)t1-heterocycle, —N(R)(CH2)t1-aryl, —N(R)(CH2)t1-heteroaryl, a carbocycle, a heterocycle, aryl and heteroaryl;
- m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13;
- n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
- r is 0 or 1
- t1 is selected from 1, 2, 3, 4, and 5;
- p1 is selected from 1, 2, 3, 4, and 5;
- q1 is selected from 1, 2, 3, 4, and 5;
- and
- s1 is selected from 1, 2, 3, 4, and 5.
The compound of any one of the preceding claims, wherein the compound is of Formula (VII):
- or its N-oxide, or a salt or isomer thereof, wherein
- l is selected from 1, 2, 3, 4, and 5;
- M1 is a bond or M′;
- and
- R2 and R3 are independently selected from the group consisting of H, C1-14 alkyl, and C2-14 alkenyl.
The compound of any one of the preceding claims, wherein the compound is of Formula (VIII):
- or its N-oxide, or a salt or isomer thereof, wherein
- l is selected from 1, 2, 3, 4, and 5;
- M1 is a bond or M′;
- and
- Ra′ and Rb′ are independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl;
- and
- R2 and R3 are independently selected from the group consisting of C1-14 alkyl, and C2-14 alkenyl.
The compound of any one of the preceding claims, wherein one of M and M′ is —S—S—, and the other is —C(O)O— or —OC(O)—.
The compound of any one of the preceding claims, wherein M is —C(O)O— or —OC(O)—.
The compound of any one of the preceding claims, wherein M is —OC(O)-M″—C(O)O—, in which M″ is C1-6 alkyl or C2-6 alkenyl.
The compound of any one of the preceding claims, wherein R1 is selected from the group consisting of —R*YR″, —YR″, and —R″M′R′.
The compound of any one of the preceding claims, wherein R′ is selected from C4 alkyl, C4 alkenyl, C5 alkyl, C5 alkenyl, C6 alkyl, C6 alkenyl, C7 alkyl, C7 alkenyl, C9 alkyl, C9 alkenyl, C11 alkyl, C11 alkenyl, C17 alkyl, C17 alkenyl, C18 alkyl, and C18 alkenyl, each of which is either linear or branched.
The compound of any one of the preceding claims, wherein R2 and R3 are the same.
The compound of any one of the preceding claims, wherein R2 and R3 are C8 alkyl.
The compound of any one of the preceding claims, wherein the compound is of the Formula (VIIa),
- or its N-oxide, or a salt or isomer thereof.
The compound of any one of the preceding claims, wherein the compound is of the Formula (VIIIa),
- or its N-oxide, or a salt or isomer thereof, wherein Rb′ is H, methyl, or ethyl.
The compound of any one of the preceding claims, wherein the compound is of the Formula (VIIIb),
- or its N-oxide, or a salt or isomer thereof, wherein Rb′ is H, methyl, or ethyl.
The compound of any one of the preceding claims, wherein the compound is of the Formula (VIIIc) or (VIIId),
- or its N-oxide, or a salt or isomer thereof, wherein Rb′ is H, methyl, or ethyl.
The compound of any one of the preceding claims, wherein r is 1.
The compound of any one of the preceding claims, wherein n is 2 or 4.
The compound of any one of the preceding claims, wherein RN is H.
The compound of any one of the preceding claims, wherein Xa is O.
The compound of any one of the preceding claims, wherein Xa is S.
The compound of any one of the preceding claims, wherein Xb is O.
The compound of any one of the preceding claims, wherein Xb is S.
The compound of any one of the preceding claims, wherein R10 is selected from the group consisting of N(R)2, —NH(CH2)t1N(R)2, —NH(CH2)p1O(CH2)q1N(R)2, —NH(CH2)s1OR, —N((CH2)s1OR)2, and a heterocycle.
The compound of any one of the preceding claims, wherein R10 is selected from the group consisting of —NH(CH2)t1N(R)2, —NH(CH2)p1O(CH2)q1N(R)2, —NH(CH2)s1OR, —N((CH2)s1OR)2, and a heterocycle.
The compound of any one of the preceding claims, wherein R10 is selected from the group consisting of —N(R)-carbocycle, —N(R)-heterocycle, —N(R)-aryl, and —N(R)-heteroaryl.
The compound of any one of the preceding claims, wherein R10 is selected from the group consisting of —N(R)(CH2)t1-carbocycle, —N(R)(CH2)t1-heterocycle, —N(R)(CH2)t1-aryl, and —N(R)(CH2)t1-heteroaryl.
The compound of any one of the preceding claims, wherein t1 is 2, 3, or 4.
The compound of any one of the preceding claims, wherein p1 is 2.
The compound of any one of the preceding claims, wherein q1 is 2.
The compound of any one of the preceding claims, wherein s1 is 2.
The compound of any one of the preceding claims, wherein R10 is morpholinyl, methyhlpiperazinyl, —NH-tetrahydropyranyl, or —NH-oxetanyl.
The compound of any one of the preceding claims, selected from compounds 340-400.
A nanoparticle composition comprising a lipid component comprising a compound according to any one of the preceding claims.
The nanoparticle composition of any one of the preceding claims, wherein the lipid component further comprises a phospholipid.
The nanoparticle composition of any one of the preceding claims, wherein the phospholipid is selected from the group consisting of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine,1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), and mixtures thereof.
The nanoparticle composition of any one of the preceding claims, wherein the lipid component further comprises a structural lipid.
The nanoparticle composition of any one of the preceding claims, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof.
The nanoparticle composition of any one of the preceding claims, wherein the lipid component further comprises a PEG lipid.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid includes a PEG moiety having a size of from about 1000 Da to about 20 kDa.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid is a compound of Formula (V):
- or a salt or isomer thereof, wherein:
- R3PEG is-ORO;
- RO is hydrogen, C1-5 alkyl or an oxygen protecting group;
- rPEG is an integer between 1 and 100;
- R5PEG is C10-40 alkyl, C10-40 alkenyl, or C10-40 alkynyl;
- and optionally one or more methylene groups of R5PEG are independently replaced with C3-10 carbocyclylene, 4 to 10 membered heterocyclylene, C6-10 arylene, 4 to 10 membered heteroarylene, —N(RN)—, —O—, —S—, —C(O)—, —C(O)N(RN)—, —NRNC(O)—, —NRNC(O)N(RN)—, —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)N(RN)—, —NRNC(O)O—, —C(O)S—, —SC(O)—, —C(═NRN)—, —C(═NRN)N(RN)—, —NRNC(═NRN)—, —NRNC(═NRN)N(RN)—, —C(S)—, —C(S)N(RN)—, —NRNC(S)—, —NRNC(S)N(RN)—, —S(O)—, —OS(O)—, —S(O)O—, —OS(O)O—, —OS(O)2—, —S(O)2O—, —OS(O)2O—, —N(RN)S(O)—, —S(O)N(RN)—, —N(RN)S(O)N(RN)—, —OS(O)N(RN)—, —N(RN)S(O)O—, —S(O)2—, —N(RN)S(O)2—, —S(O)2N(RN)—, —N(RN)S(O)2N(RN)—, —OS(O)2N(RN)—, or —N(RN)S(O)2O—;
- and
- each instance of RN is independently hydrogen, C1-6 alkyl, or a nitrogen protecting group.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid is a compound of Formula (V-a):
- or a salt or isomer thereof.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid is a compound of Formula (VI-b):
- or a salt or isomer thereof.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid is a compound having the formula:
- or a salt or isomer thereof, wherein rPEG1 is an integer between 40 and 50.
The nanoparticle composition of any one of the preceding claims, wherein the PEG lipid is a compound having the formula:
- or a salt or isomer thereof.
The nanoparticle composition of any one of the preceding claims, wherein the lipid component further comprises a cationic and/or ionizable lipid selected from the group consisting of 3-(didodecylamino)—N1,N1,4-tridodecyl-1-piperazineethanamine (KL10), N1-[2-(didodecylamino)ethyl]—N1,N4,N4-tridodecyl-1,4-piperazinediethanamine (KL22), 14,25-ditridecyl-15,18,21,24-tetraaza-octatriacontane (KL25), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (DLin-MC3-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 2-({8-[(30)-cholest-5-en-3-yloxy]octyl}oxy)—N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (Octyl-CLinDMA), (2R)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)—N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (Octyl-CLinDMA (2R)), and (2S)-2-({8-[(3p)-cholest-5-en-3-yloxy]octyl}oxy)—N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (Octyl-CLinDMA (2S)).
The nanoparticle composition of any one of the preceding claims, wherein the lipid component comprises about 30 mol % to about 60 mol % said compound, about 0 mol % to about 30 mol % phospholipid, about 18.5 mol % to about 48.5 mol % structural lipid, and about 0 mol % to about 10 mol % PEG lipid.
The nanoparticle composition of any one of the preceding claims, wherein the lipid component comprises about 50 mol % said compound, about 10 mol % phospholipid, about 38.5 mol % structural lipid, and about 1.5 mol % PEG lipid.
The nanoparticle composition of any one of the preceding claims, further comprising a therapeutic and/or prophylactic agent.
The nanoparticle composition of any one of the preceding claims, wherein the therapeutic and/or prophylactic agent is a vaccine or a compound capable of eliciting an immune response.
The nanoparticle composition of any one of the preceding claims, wherein the therapeutic and/or prophylactic agent is a nucleic acid.
The nanoparticle composition of any one of the preceding claims, wherein the therapeutic and/or prophylactic agent is a ribonucleic acid (RNA).
The nanoparticle composition of any one of the preceding claims, wherein the RNA is selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and mixtures thereof.
The nanoparticle composition of any one of the preceding claims, wherein the RNA is an mRNA.
The nanoparticle composition of any one of the preceding claims, wherein the mRNA includes one or more of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and/or a 5′ cap structure.
The nanoparticle composition of any one of the preceding claims, wherein the encapsulation efficiency of the therapeutic and/or prophylactic agent is at least 50%, at least 80%, or at least 90%.
The nanoparticle composition of any one of the preceding claims, wherein the wt/wt ratio of the lipid component to the therapeutic and/or prophylactic agent is from about 10:1 to about 60:1.
The nanoparticle composition of any one of the preceding claims, wherein the wt/wt ratio of the lipid component to the therapeutic and/or prophylactic agent is about 20:1.
The nanoparticle composition of any one of the preceding claims, wherein the N:P ratio is from about 2:1 to about 30:1.
The nanoparticle composition of any one of the preceding claims, wherein the N:P ratio is about 5.67:1.
The nanoparticle composition of any one of the preceding claims, wherein the mean size of the nanoparticle composition is from about 70 nm to about 100 nm.
The nanoparticle composition of any one of the preceding claims, wherein the polydispersity index of the nanoparticle composition is from about 0.10 to about 0.20.
The nanoparticle composition of any one of the preceding claims, wherein the nanoparticle composition has a zeta potential of about −10 mV to about +20 mV.
The nanoparticle composition of any one of the preceding claims, wherein the nanoparticle has a surface pKa of about 6.6.
The nanoparticle composition of any one of the preceding claims, wherein the nanoparticle has an endosomal escape efficiency of about 15%.
A pharmaceutical composition comprising the nanoparticle composition of any one of the preceding claims and a pharmaceutically acceptable carrier.
A method of delivering a therapeutic and/or prophylactic agent to a mammalian cell, the method comprising administering to a subject the nanoparticle composition of any one of the preceding claims, said administering comprising contacting the cell with the nanoparticle composition, whereby the therapeutic and/or prophylactic agent is delivered to the cell.
A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the nanoparticle composition of any one of the preceding claims, wherein the therapeutic and/or prophylactic agent is an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
A method of treating a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the nanoparticle composition of any one of the preceding claims.
A method of specifically delivering a therapeutic and/or prophylactic agent to a mammalian organ, the method comprising administering to a mammal the nanoparticle composition of any one of the preceding claims, said administering comprising contacting the mammalian organ with the nanoparticle composition, whereby the therapeutic and/or prophylactic agent is delivered to the organ.
The nanoparticle composition of any one of the preceding claims, for use in the treatment of a disease or disorder in a mammal in need thereof.
The nanoparticle composition of any one of the preceding claims, for use as a medicament for the treatment of a disease or disorder in a mammal in need thereof.
The use of a nanoparticle composition of any one of the preceding claims, in the manufacture of a medicament for the treatment of a disease or disorder in a mammal in need thereof.
The method, use, or nanoparticle composition for use of any one of the preceding claims, wherein the disease or disorder is characterized by dysfunctional or aberrant protein or polypeptide activity.
The method, use, or nanoparticle composition for use of any one of the preceding claims, wherein the disease or disorder is selected from the group consisting of infectious diseases, cancer and proliferative diseases, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardio- and reno-vascular diseases, and metabolic diseases.
The method, use, or nanoparticle composition for use of any one of the preceding claims, wherein the mammal is a human.
The method, use, or nanoparticle composition for use of any one of the preceding claims, wherein the nanoparticle composition is administered intravenously, intramuscularly, intradermally, subcutaneously, intranasally, or by inhalation.
The method, use, or nanoparticle composition for use of any one of the preceding claims, wherein the nanoparticle composition is administered subcutaneously.
The method, use, or nanoparticle composition for use of any one of the preceding claims, wherein a dose of about 0.001 mg/kg to about 10 mg/kg of the therapeutic and/or prophylactic agent is administered to the mammal, or wherein the medicament comprises 0.001 mg/kg to about 10 mg/kg of the therapeutic and/or prophylactic agent.
The method of any one of the preceding claims, further comprising, prior to the contacting or administering step, pretreating said mammal with one or more additional compounds, wherein pretreating comprises administering said one or more additional compounds to said mammal.
The method of any one of the preceding claims, wherein said mammal is pretreated two weeks or fewer, one week or fewer, 24 or fewer hours prior to the contacting or administering step.
The method of any one of the preceding claims, wherein said mammal is pretreated about one hour prior to the contacting or administering step.
The method of any one of the preceding claims, wherein said one or more additional compounds are selected from the group consisting of anti-inflammatory compounds, steroids, statins, estradiols, BTK inhibitors, S1P1 agonists, glucocorticoid receptor modulators (GRMs), and anti-histamines.
The method of any one of the preceding claims, wherein said one or more additional compounds are selected from the group consisting of dexamethasone, methotrexate, acetaminophen, an H1 receptor blocker, and an H2 receptor blocker.
Dependencies are inferred from the claim text.