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Review
. 2021 Apr 16:12:623674.
doi: 10.3389/fphar.2021.623674. eCollection 2021.

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era

Mengda Xu  1   2 , Jiangping Song  1
Affiliations
Review

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era

Mengda Xu et al. Front Pharmacol. .

Erratum in

Abstract

Targeted therapy refers to exploiting the specific therapeutic drugs against the pathogenic molecules (a protein or a gene) or cells. The drug specifically binds to disease-causing molecules or cells without affecting normal tissue, thus enabling personalized and precision treatment. Initially, therapeutic drugs included antibodies and small molecules, (e.g. nucleic acid drugs). With the advancement of the biology technology and immunotherapy, the gene editing and cell editing techniques are utilized for the disease treatment. Currently, targeted therapies applied to treat cardiovascular diseases (CVDs) mainly include protein drugs, gene editing technologies, nucleic acid drugs and cell therapy. Although targeted therapy has demonstrated excellent efficacy in pre-clinical and clinical trials, several limitations need to be recognized and overcome in clinical application, (e.g. off-target events, gene mutations, etc.). This review introduces the mechanisms of different targeted therapies, and mainly describes the targeted therapy applied in the CVDs. Furthermore, we made comparative analysis to clarify the advantages and disadvantages of different targeted therapies. This overview is expected to provide a new concept to the treatment of the CVDs.

Keywords: antibody; cardiovascular disease; cell therapy; gene editing; nucleic acid drugs; targeted therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Mechanisms of the mAb. (A) The Fab of the mAb binds to the target epitope and the Fc of the mAb binds to the effector cell (such as the natural killer cell) or the complement to kill the target cells through antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity or directly inhibit abnormal signals of the target cells. (B) The mAb binds to the growth factor (such as VEGF) to inhibit the angiogenesis of the target cells. (C) The interaction between some ligands and receptors (such as PD-1/PD-L1) can inactivate the effector cells. The mAb binds to the inhibitory molecule to protect the effector cells from dysfunction. (D) The mAbs are equipped with radiopharmaceuticals or chemotherapeutic drugs. When the mAbs binds to the target cells, the drugs come close to the target cell and kill the target cells.
FIGURE 2
FIGURE 2
Mechanisms of the bAb. (A) Bridging cell. The bAb binds to two different cells at the same time, thus dragging these two cells closer. (B) Bridging receptor. The bAb binds to two different proteins on the cell surface and plays a synergistic role, thus inactivating the target cell more efficiently. (C) Cofactor simulation. The bAb binds to target antigen and plays the role of agonist to treat diseases. (D) Piggyback mode. One of the antigen binding parts of the bAb combines with the target molecule, while the other antigen binding part of the bAb binds to the specific area. In this way, the molecule is transported to the specific area.
FIGURE 3
FIGURE 3
Mechanism of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated protein 9 (Cas9): When viruses and foreign DNA invade the host, the cas1 and cas2 protein can recognize the protospacer adjacent motif (PAM) region. The cas1/2 protein will cut the PAM and insert it into the downstream of the leader sequence of CRISPR. When the same sequence invades the host, the transcription of precursor CRISPR RNA (pre-crRNA) and trans-activating crRNA (tracrRNA) will be activated. The pre-crRNA, tracrRNA and the cas9 will form a complex that can recognize the sequence that is complementary to the crRNA. After the recognition, the double-strand DNA unwinds to form an R-loop. The crRNA combines with the target sequence via base pairing. Then the double-strand-break (DSB) is induced by the cas9 protease. In the CRISPR/Cas9 gene editing technology, the sgRNA consisting of the tracrRNA and the crRNA is designed in vitro. The sgRNA will guide the cas9 to a specific DNA sequence to cause the DSB. After the DSB, endogenous DNA repairs systems (nonhomologous end joining in both dividing and nondividing cells, homology directed repair in the G2/S phase of dividing cells) result in the gene knock-in or knock-out.
FIGURE 4
FIGURE 4
Mechanisms of CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa): The cas protein in the CRISPRi/a is catalytically inactivated (called dcas9). In the CRISPRi, the dcas9 connects with transcriptional suppressors, such as Kruppel associated box (KRAB). Under the guidance of gRNA, the dcas9-KRAB fusion protein binds to the transcription start site (TSS) of the target gene and inhibits transcription. On the contrary, the dcas9 of the CRISPRa is equipped with the transcriptional activator to a given TSS.
FIGURE 5
FIGURE 5
Mechanism of RNA interference (RNAi): RNAi is a post-transcriptional gene silencing method. The microRNA (miRNA) and small interfering RNA (siRNA) can mediate the RNAi. The miRNA is a kind of endogenous non-coding RNA. The miRNA-mediated RNAi starts from the generation of the pri-miRNA. When generated endogenously, the pri-miRNA is cut by the drosha and DGCR8, resulting in the formation of the pre-miRNA. After that, the pre-miRNA is transported into the cytoplasm. Dicer recognizes the pre-miRNA and cuts it into a single strand. Finally, the transactivation response element RNA-binding protein (TRBP), Dicer, Argonaute protein, and the miRNA form the RNA induced silencing complex (RISC). The RISC will bind the complementary mRNA to inhibit the translation. The siRNA is a kind of exogenous non-coding RNA. After delivered into the cells, the siRNA will be cleaved into a single strand RNA. After that, the TRBP, Dicer, Argonaute protein and the siRNA form the RISC. The RISC will degrade the complementary mRNA.
FIGURE 6
FIGURE 6
Mechanisms of Chimeric antigen receptor T-cell (CAR-T) therapy. The CAR is made up of three components: 1) an antigen binding region, which consists of a single-chain fragment variable (scFv). The scFv can specifically target to the antigens. 2) the transmembrane area, which fixes the scFv on the surface of T cells. 3) signal transduction region, which consists of CD3-ζ chain of the T cell. The gene of the CAR is designed based on the target antigen. After that, the T cells were extracted from the patients and transfected by vectors carrying the CAR gene. The transfection results in the expression of the CAR on the surface of T cells (CAR-T cells). The CAR-T cells are amplified in vitro and injected into the patients to cure the disease.
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Grants and funding

This work was supported by Fundamental Research Funds for the Central Universities, Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1-015).

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