CN-121987803-A - Lipid composition and application thereof in nucleic acid delivery

Abstract

The invention discloses a lipid composition and application thereof in nucleic acid delivery. The lipid composition can be used to deliver siRNA by intra-articular or subcutaneous administration, with the aim of achieving an arthritic therapeutic effect superior to that of the existing commercial formulation of lipid compositions. The lipid composition provided by the invention can be used for delivering nucleic acid medicines, compared with the LNP formula which is marketed, the lipid composition reduces the ratio of ionizable cationic lipid and increases the ratio of PEG lipid. The lipid composition shows a better effect in the treatment of collagen-induced arthritis (CIA) in rats, particularly by injecting or subcutaneously injecting through joint cavities when siRNA for the treatment of autoimmune diseases is delivered, and significantly reduces the arthritis score and foot volume.

Inventors

• WU JIE
• XU SONGLIN
• SHI MENGCHAO
• LI PING

Assignees

• 羿美诚健(上海)生物医药有限公司

Dates

Publication Date

20260508

Application Date

20260109

Claims (10)

1. 1. The lipid composition is characterized by comprising an ionizable cationic lipid, a neutral auxiliary lipid, cholesterol and a PEG lipid, wherein the mole ratio of the ionizable cationic lipid to the neutral auxiliary lipid to the cholesterol to the PEG lipid is 37-49:8-22:38-39:2-6, the ionizable cationic lipid is selected from Dlin-MC3-DMA、DODMA、SM-102、ALC-0315、DLin-KC2-DMA、DLin-KC3-DMA、DLinDMA、DLenDMA、DLin-MC2-DMA、DLinDAP、DMDAP and DODAP, the neutral auxiliary lipid is DSPC, and the PEG lipid is DMG-PEG2000.
2. 2. The lipid composition of claim 1, wherein the lipid composition is used as a delivery vehicle for nucleic acids.
3. 3. The lipid composition of claim 1, wherein the nucleic acid is RNA.
4. 4. Use of a lipid composition according to any one of claims 1 to 3 in the preparation of a medicament for the treatment of arthritis, wherein the molar ratio of ionizable cationic lipid, DSPC, cholesterol and DMG-PEG2000 in the lipid composition is 37.5 to 40.5:17 to 20.5:38 to 39:3 to 5 or 46.5 to 48.5:9.5 to 10.5:38 to 39:3 to 5.
5. 5. The method of claim 4, wherein the ionizable cationic lipid is Dlin-MC3-DMA, and the lipid composition is used as a delivery vehicle for the intra-articular injection administration of nucleic acids, or wherein the ionizable cationic lipid is selected from DODMA, SM-102, AL-0315, DLin-KC2-DMA, DLin-KC3-DMA, DLinDMA, DLenDMA, DLin-MC2-DMA, DLinDAP, DMDAP, and DODAP.
6. 6. The use according to claim 4, wherein the arthritis is rheumatoid arthritis.
7. 7. A pharmaceutical composition comprising a nucleic acid and the lipid composition of any one of claims 1 to 3, wherein the mass ratio of lipid composition to nucleic acid is 8 to 20:1.
8. 8. The method of treating arthritis, wherein the ionizable cationic lipid in the lipid composition is selected from Dlin-MC3-DMA、DODMA、SM-102、AL-0315、DLin-KC2-DMA、DLin-KC3-DMA、DLinDMA、DLenDMA、DLin-MC2-DMA、DLinDAP、DMDAP and DODAP, and the mole ratio of the ionizable cationic lipid, DSPC, cholesterol and DMG-PEG2000 in the lipid composition is 37.5-40.5:17-20.5:38-39:3-5 or 46.5-48.5:9.5-10.5:38-39:3-5.
9. 9. The use according to claim 8, wherein the ionizable cationic lipid is Dlin-MC3-DMA and the lipid composition is used as a delivery vehicle for the intra-articular injection administration of nucleic acids, or wherein the ionizable cationic lipid is selected from DODMA, SM-102, AL-0315, DLin-KC2-DMA, DLin-KC3-DMA, DLinDMA, DLenDMA, DLin-MC2-DMA, DLinDAP, DMDAP and DODAP and the lipid composition is used as a delivery vehicle for the subcutaneous injection administration of nucleic acids.
10. 10. The use according to claim 8, wherein the arthritis is rheumatoid arthritis.

Description

Lipid composition and application thereof in nucleic acid delivery Technical Field The invention belongs to the technical field of biological medicine, and particularly relates to an LNP composition and application thereof in nucleic acid delivery. Background Autoimmune diseases are diseases in which the immune system of the organism generates immune response to its own tissues and organs and causes tissue injury and dysfunction, and the occurrence mechanism of the autoimmune diseases is complex and mainly comprises two factors of genetics and environment. Most autoimmune diseases are polygenic, e.g., people who contain a series of genetic mutations in antigen presentation, chemotaxis, or B-cell and T-cell signaling processes are more susceptible to autoimmune diseases. Genetic mutations can cause a predisposition to immune imbalance in patients, and environmental factors are important links in the induction of morbidity. Foreign antigens in the environment can cause false immune activation, and induce autoimmune diseases. In summary, the complex mechanisms of occurrence present challenges for the treatment of autoimmune diseases. Traditional therapeutic drugs for autoimmune diseases are mainly anti-inflammatory drugs, including antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and the like, and have good anti-inflammatory effects but can treat symptoms without root cause and easily relapse after drug withdrawal. In recent years, biological targeting drugs are becoming better choices for treating autoimmune diseases, but the biological targeting drugs are also accompanied by the defects of safety risks (the risk of malignant tumors possibly increasing after long-term use and the possibility of inducing new autoimmune diseases), inconvenient administration modes, limited patient compliance, high treatment cost and the like. SiRNA also belongs to one of biological targeting drugs, but no siRNA lipid nano-drug is currently marketed for the treatment of autoimmune diseases. Based on RNAi mechanism, siRNA can target specific genes to realize accurate treatment, has the characteristics of high efficiency, sequence specificity and transiently, however, high-efficiency delivery to targets is always one of difficulties in siRNA drug development. Lipid nanoparticles (LNP, lipid Nanoparticles) are one of the most widely used carriers for siRNA delivery at present, and there are many siRNA drugs on the market (e.g. PATISIRAN for treating hereditary transthyretin amyloidosis) which use LNP as a delivery carrier. However, despite successful clinical use, LNP has limitations as a delivery vehicle, such as insufficient targeting, susceptibility to liver enrichment, and difficulty in delivery to specific tissues such as lung, brain, tumor, etc. As can be seen, in order to better apply siRNA to the treatment of autoimmune diseases, there is still a need to develop more accurate and efficient delivery systems for siRNA delivery. Disclosure of Invention To remedy the deficiencies of the prior art, the present invention provides a lipid composition that is administered via the joint cavity or subcutaneously, and is used to deliver siRNA, aiming to achieve an arthritis therapeutic effect superior to the commercial formulation of the existing lipid composition (Dlin-MC 3-DMA: DSPC: cholesterol: DMG-pe2000=50:10:38.5:1.5). In one aspect, the present invention provides a lipid composition comprising an ionizable cationic lipid, a neutral helper lipid, cholesterol, and a PEG lipid; the mole ratio of the ionizable cationic lipid, neutral auxiliary lipid, cholesterol and PEG lipid in the lipid composition is 37-49:8-22:38-39:2-6, the ionizable cationic lipid is selected from (6Z, 9Z, 28Z, 31Z) -heptadecan-6, 9, 28, 31-tetraen-19-yl 4- (dimethylamino) butyrate (Dlin-MC 3-DMA), 1, 2-dioleyloxy-N, N-dimethylaminopropane (DODMA), heptadec-9-yl-8- ((2-hydroxyethyl) (6-oxo-6- ((undecyloxy) hexyl) amino) caprylate) (SM-102), ((4-hydroxybutyl) azadialkyl) bis (hexane-6, 1-diyl) bis (2-hexyldecanoate) (ALC-0315), 2-diileyl-4- (2-dimethylaminoethyl) - [1,3] -dioxacyclopentane (in-KC-2, 2-dioleyloxy-N, N-dimethylaminopropane (DODMA), heptadec-9-yl-8- ((2-hydroxyethyl) (6-oxo-6- ((undecyloxy) hexyl) amino) caprylate) (SM-102), ((4-hydroxybutyl) azadialkyl) bis (hexane-6, 1-diyl) bis (2-hexyl decanoate) (DLL-0315) 1, 2-di-linolenyloxy-N, N-dimethylaminopropane (DLenDMA), di-linoleylmethyl-3-dimethylaminopropionate (DLin-MC 2-DMA), 1, 2-di-linoleoyl-3-dimethylaminopropane (DLinDAP), 1, 2-dimyristoyl-3-dimethylaminopropane (DMDAP) and 1, 2-dioleoyl-3-dimethylpropylamine (DODAP), the neutral helper lipid being 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC), the PEG lipid being 1, 2-dimyristoyl-sn-glycero-methoxypolyethylene glycol (DMG-PEG 2000). Preferably, the molar ratio of the ionizable cationic lipid, the neutral auxiliary lipid, the cholesterol and the PEG lipid in the lipid composition is 37.5-