Gene therapy for polygenic or complex diseases

Abstract

Gene therapy utilizes nucleic acid drugs to treat diseases, encompassing gene supplementation, gene replacement, gene silencing, and gene editing. It represents a distinct therapeutic approach from traditional medications and introduces novel strategies for genetic disorders. Over the past two decades, significant advancements have been made in the field of gene therapy, leading to the approval of various gene therapy drugs. Gene therapy was initially employed for treating genetic diseases and cancers, particularly monogenic conditions classified as orphan diseases due to their low prevalence rates; however, polygenic or complex diseases exhibit higher incidence rates within populations. Extensive research on the etiology of polygenic diseases has unveiled new therapeutic targets that offer fresh opportunities for their treatment. Building upon the progress achieved in gene therapy for monogenic diseases and cancers, extending its application to polygenic or complex diseases would enable targeting a broader range of patient populations. This review aims to discuss the strategies of gene therapy, methods of gene editing (mainly CRISPR-CAS9), and carriers utilized in gene therapy, and highlight the applications of gene therapy in polygenic or complex diseases focused on applications that have either entered clinical stages or are currently undergoing clinical trials.

Keywords: CRISPR-CAS9; Complex diseases; Gene therapy; Polygenic diseases.

Fig. 1

To illustrate the ex vivo gene therapy approach, we employ sickle cell anemia as a paradigm for gene therapy. Casgevy: Initially, CD34 + hematopoietic stem and progenitor cells were isolated from the patient. Precise gene editing was performed on the patient's hematopoietic stem cells by specifically targeting the erythroid enhancer region of BCL11A using a single-guide RNA molecule (sgRNA). Subsequently, the edited cells were reintroduced into the patient's body with the aim of combating sickle cell anemia through increased expression of HbF. Lyfgenia: The BB305 lentiviral vector was employed to transduce modified β-globin genes into hematopoietic stem cells, resulting in the production of HbAT87Q—a hemoglobin variant that is resistant to disease and capable of inhibiting sickle hemoglobin polymerization. The remaining steps remain consistent with those described by Casgevy. Created with BioRender.com

Fig. 2

Gene therapy strategies for cardiovascular diseases. VEGF: Vascular endothelial growth factor; FGF: Fibroblast growth factor family; HGF: Hepatocyte growth factor; SDF-1: Stromal cell-derived factor 1; Ang: Angiotensin; SERCA2a: Sarcoplasmic/endoplasmic reticulum Ca2 + ATPase. Created with BioRender.com

Fig. 3

The targets for gene therapy in the treatment of hyperlipidemia. PCSK9, acting as a partner of the LDL receptor, facilitates the trafficking of the LDL receptor to the lysosome, thereby enhancing its degradation. Inclisiran is a siRNA-based drug targeting PCSK9, it hampers the degradation process of the LDL receptor and promotes its recycling instead, ultimately leading to reduced levels of LDL. Olpasiran is a siRNA-based agent that effectively impedes the hepatic assembly of Lp(a) by downregulating its expression in hepatocytes, Pelacarsen is an oligonucleotide drug that inhibits the synthesis of apo(a), resulting in a dose-dependent reduction in Lp(a) levels. Vupanorsen and Volanesorsen are ASO drugs targeting ANGPTL3 and ApoC-III respectively. Lp(a): Lipoprotein(a); VLDL: Very low-density lipoprotein; IDL: Intermediate-density lipoprotein; LDL: Low-density lipoprotein; PCSK9: Proprotein convertase subtilisin/kexin type 9; APOC3: Apolipoprotein C-III; ANGPTL3: Angiopoietin-like protein; ASO: Antisense oligonucleotides; LPL: Lipoprotein lipase. Created with BioRender.com

Fig. 4

Strategies for tumor gene therapy. GM-CSF: Granulocyte–macrophage colony-stimulating factor; CAR-T: Chimeric antigen receptor T-cell; NK: Natural killer cell. Created with BioRender.com