Table 1.
Cutting-edge therapeutic approaches that target lipoprotein metabolism.
| Category | Strategy | Target | Method | Models | Therapeutic effect | Refs. |
|---|---|---|---|---|---|---|
| mAbs | PCKS9 | PCKS9 silencing | In vitro and apoliporotein E knockout mice | (1) proinflammatory cytokine downregulation (2) TLR4/NF-ĸβ inhibition |
[129] | |
| Alirocumab | APOE*3Leiden.CETP mice. | (1) decreasing the lipid component of non-culprit plaques (2) stabilize plaque |
[130, 132] | |||
| Alirocumab | Clinical trial | (1) reduced mortality (2) reduced risk of stroke and myocardial infarction (MI) |
[131] | |||
| Bocociziumab | Parallel and randomized clinical trials | (1) reduced the LDL levels in most patients with hyperlipidemia at 3 months | [133] | |||
| Evolocumab | Clinical trials | (1) reduce the cholesterol levels by an average of 0.7mmol/l (2) reduce the risk of cardiovascular events |
[135] | |||
| ANGPTL3 | Evinacumab | Phase 2 clinical trial | (1) 49% reduction in LDL-C (2) <80% reduction in triglycerides |
[143] | ||
| Evinacumab | Clinical trial | (1) benefit for patients with LDL receptor mutations (2) 34% reduction in LDL-C of patients with biallelic null LDL receptor mutations |
[144] | |||
| Vaccine | Cholesterol lowering | PCKS9 | Inclisiran | Phase III clinical trial | (1) inhibition of PCKS9 (2) 50% reduction in LDL-C (3) injection-site adverse events |
[155, 156] |
| Peptide based AT04A | APOE*3Leiden.CETP mice | (1) reduction in plasma lipids (2) decreased inflammatory response (3) diminished atherosclerotic lesions |
[157] | |||
| ApoC3 | ISIS 304801 (Antisense DNA) | Clinical trial | (1) decrease in triglyceride levels | [158] | ||
| VLPs | Mice | (1) reduction in plasma lipid level | [159] | |||
| CETP | Rabbit | (1) 24% reduction in LDL-C (2) 39.6% reduction of atherosclerotic lesions |
[160] | |||
| CETi-1 | Phase I clinical trial | (1) insignificant reduction in HDL | [161] | |||
| Antigen-inducing | HSP65 | Lactococcus lactis | LDL receptor deficient mice | (1) upregulation of IL10 (2) downregulation of IFN-γ (3) atheroprotection |
[163] | |
| HSP60 | Porphyromonas gingivalis | Hyperlipidaemia (Apoeshl) mice | (1) increase in IL-10 (2) reduction in CRP, MCP-1. Ox-LDL (3) inhibition in atherosclerotic lesion formation |
[164] | ||
| Ox-LDL | Hypercholesterolemia rabbits | (1) reduction in atherosclerotic lesion size (2) increase in ox-LDL antibodies |
[152] | |||
| LDL ox-LDL |
Hypercholesterolemia rabbits | (1) ox-LDL antibodies increase in both LDL and ox-LDL immunized rabbits (2) 74% reduction in atherosclerotic lesions in LDL immunized rabbit (3) 48% reduction in lesions in ox-LDL immunized rabbit |
[153] | |||
| ox-LDL LDL |
Hypercholesterolemia rabbits | (1) 58% reduction in the neointial area in ox-LDL immunized rabbit (2) 19% reduction in the neointimal area in LDL immunized rabbit (3) reduced T cells and ox-LDL in ox-LDL immunized rabbit |
[165] | |||
| MDA-LDL | Apo-E-deficient mice | (1) upregulation of MDA-LDL antibodies (2) reduced lesion size at the aortic sinus |
[166] | |||
| ApoB-100 | P210 | ApoE-Null Mice | (1) 60% reduction in atherosclerotic lesion (2) increase in collagen content of subvalvular lesions |
[168] | ||
| P45, P74 | ApoE deficient mice | (1) P45 reduced the atherosclerosis by 48% and reduced the macrophage in lesion by 33% (2) P74 decrease the lesion by 3% and macrophage content by 39% |
[170] | |||
| Multitarget | Apob-100 HSP60 |
P45 and Chylamydophia pneumonia | Ldlr-/-mice | (1) reducing lesion size wihouth Cpn infection (2) downregulation of cellular infiltration, and inflammatory cytokine/chemokine section |
[172] | |
| Gene-therapy | ASO based | ApoB mRNA | Mipomersen | Clinical trials | (1) 24.7% reduction in LDL-C (2) adverse effects: flu like side effect, liver steatosis, injection site reaction |
[173] |
| Apo(a) mRNA | IONIS-APO(a)-LRX | Clinical trials | (1) 71.6% reduction in Lp(a) level | [178] | ||
| AKCEA-APO(a)-LRx (TQJ230) | Clinical trial Phase III | 80% reduction in Lp(a) level | [179] | |||
| ApoC3 mRNA | Volanesorsen | Phase III clinical trial | 77% decrease in triglycerides | [180] | ||
| ANGPTL3 | IONIS-ANGPTL3-LRX | Phase II clinical trial | (1) 33.2-63.1% reduction in triglycerides (2) 1.3-32.9% reduction in LDL-C (3) 27.9-60% reduction in VLDL-C |
[181] | ||
| Viral mediated | LPL | Glybera (AAV1) | Clinical trial | (1) reduced pancreatitis events (2) decreased acute abdominal pain events associated with panceratitis (3) discontinued |
[185] | |
| LDLR | AAV8 | Humanized mouse models of familial hypercholesterolemia | Significant reduction in LDL-C level | [188] | ||
| Humanized mouse model of familial hypercholesterolemia | (1) reduction in plasma cholesterol and non-HD-C level (2) 87% reduction in lesions after 3 months (3) significant remodelling of lesion |
[187] | ||||
| Phase I clinical trial | (1) limited toxicity and no signification upregulation of pro-inflammatory cytokines | [189] | ||||
| ApoA-I | HD-Ad | Apo E-deficient mice | (1) upregulation of APOA-I expression and HDL-C (2) reduction in lesion size |
[191] | ||
| Rabbit | (1) 70% reduction in plasm cholesterol (2) 208% reduction in VACM-1 expression (3) 30% reduction in macrophage content (4) reduction in lesion size, lipid content and ICAM-1 expression |
[192] | ||||
| Hyperlipidemic rabbits | (1) apoA-I mRNA expression (2) reduction in lesion size, lipid/macrophage content (3) downregulation of adhesion molecule expression |
[193] | ||||
| Hyperlipidemic rabbits | (1) 30% reduction in intimal lesion volume (2) 23-32% reduction in intimal lipid, macrophage and SMCs contents (3) 36% reduction in VACM-1 expression (4) downregulation of ICAM-1, MCP-1 and TNF-α |
[194] | ||||
| Genome/base editing | LD-R | AAV-8 mediated CRISPER/Cas 9 | Adult mice | (1) development of hypercholesterolemia adds atherosclerosis | [201, 202] | |
| PCKS9 | S. pyogenes Cas9 in adenoviral vector | Mice | (1) decrease in PCSK9 level (2) increase in hepatic LDL receptor level (3) 35-40% reduction in serum cholesterol levels |
[203] | ||
| aureus Cas9 in AAV | Mice | (1) over 40% gene modification (2) reduction in PCSK9 and cholesterol levels |
[204, 205] | |||
| Streptococcus pyogenes Cas9 | Mice | reduced peptides, decreased indels and no chromosomal translocation in addition to reduced TC levels | [203] | |||
| ANGPTL3 | Mice | (1) 56% reduction in triglycerides (2) a 51% decrease in LDL-C |
[207] |