Novel vectors and approaches for gene therapy in liver diseases

Maestro, Sheila; Weber, Nicholas; Zabaleta, Nerea; Aldabe, Rafael; González‐Aseguinolaza, Gloria

doi:10.1016/j.jhepr.2021.100300

Cited by 78 publications

(87 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the disadvantages of miRNAs, such as poor stability, inability to penetrate cell membranes, and low specificity, severely restrict their applications 9 . At present, the commonly used miRNA delivery vehicles include viral transfection and liposome delivery, but the biological safety of viral transfection is low, and the use of liposomes as miRNA delivery vehicles confers certain cytotoxicity 37 . Therefore, finding an ideal carrier to safely and efficiently transfect exogenous miRNAs that can promote osteogenic differentiation into ADSCs, and conduct in‐depth research on the specific regulatory mechanism has become an important breakthrough in the regeneration and treatment of bone tissue defects.…”

Section: Discussionmentioning

confidence: 99%

MiR‐26a‐tetrahedral framework nucleic acids mediated osteogenesis of adipose‐derived mesenchymal stem cells

et al. 2022

View full text Add to dashboard Cite

Objectives: Delivery systems that provide time and space control have a good application prospect in tissue regeneration applications, as they can effectively improve the process of wound healing and tissue repair. In our experiments, we constructed a novel micro-RNA delivery system by linking framework nucleic acid nanomaterials to micro-RNAs to promote osteogenic differentiation of mesenchymal stem cells. Materials and Methods:To verify the successful preparation of tFNAs-miR-26a, the size of tFNAs-miR-26a were observed by non-denaturing polyacrylamide gel electrophoresis and dynamic light scattering techniques. The expression of osteogenic differentiation-related genes and proteins was investigated by confocal microscope, PCR and western blot to detect the impact of tFNAs-miR-26a on ADSCs. And finally, Wnt/β-catenin signaling pathway related proteins and genes were detected by confocal microscope, PCR and western blot to study the relevant mechanism.Results: By adding this novel complex, the osteogenic differentiation ability of mesenchymal stem cells was significantly improved, and the expression of alkaline phosphatase (ALP) on the surface of the cell membrane and the formation of calcium nodules in mesenchymal stem cells were significantly increased on days 7 and 14 of induction of osteogenic differentiation, respectively. Gene and protein expression levels of ALP (an early marker associated with osteogenic differentiation), RUNX2 (a metaphase marker), and OPN (a late marker) were significantly increased. We also studied the relevant mechanism of action and found that the novel nucleic acid complex promoted osteogenic differentiation of mesenchymal stem cells by activating the canonical Wnt signaling pathway.Conclusions: This study may provide a new research direction for the application of novel nucleic acid nanomaterials in bone tissue regeneration.

show abstract

Section: Discussionmentioning

confidence: 99%

MiR‐26a‐tetrahedral framework nucleic acids mediated osteogenesis of adipose‐derived mesenchymal stem cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Gene therapy has emerged as a promising approach to achieve safe, stable, and efficient long-term correction for a wide range of genetic diseases [ 85 ], including monogenic liver disorders, for which liver transplantation remains the only cure [ 86 ], as well as acquired liver diseases [ 87 ]. Viral and non-viral vectors have shown promising therapeutic results in numerous clinically relevant animal models, as well as in a large number of clinical trials [ 88 , 89 ]. The fact that more than a dozen gene therapy products have been approved by the FDA and EMA, albeit only three for liver gene therapy, is a promising sign for the future application of this technology for liver disorders [ 90 , 91 ].…”

Section: Gene Therapymentioning

confidence: 99%

“…Gene therapy for the treatment of inherited hepatic diseases has garnered a great deal of attention after demonstrating that AAV vectors expressing human coagulation factors IX and VIII in the livers of patients with hemophilia B and A, respectively, resulted in a sustained therapeutic effect for more than three years [ 103 ]. In fact, a large number of gene therapy products have demonstrated promising therapeutic effects in clinically relevant animal models, leading to clinical trials for inherited liver disorders, such as phenylketonuria, familial hypercholesterolemia, ornithine transcarbamylase deficiency, acute intermittent porphyria, methylmalonic acidemia, and Wilson’s disease, among others [ 88 ]. In the next sections of the review, we will focus on the use of gene therapy for inherited cholestatic diseases, which include genetic disorders with associated cholestasis and the different forms of PFIC.…”

Section: Gene Therapymentioning

confidence: 99%

“…And finally, for those cholestatic disorders in which correction of the majority of hepatocytes for a long-term therapeutic effect is likely necessary, as in the case of some PFIC subtypes [ 108 , 109 ], a promising alternative is the use of CRISPR/Cas9 to achieve specific gene correction by non-homologous end-joining, base editing, or prime editing. The high efficiency of liver-targeted gene delivery makes it an ideal organ for the application of gene editing strategies in animal models of PFIC [ 88 ]. However, there are still many barriers hampering the use of gene editing techniques in humans, such as reduced specificity of targeted integration leading to safety concerns, as well as the low efficacy of non-homologous end-joining [ 137 ].…”

Section: Future Directionsmentioning

confidence: 99%

See 1 more Smart Citation

Gene Therapy for Acquired and Genetic Cholestasis

Martínez-García

Molina

González‐Aseguinolaza

et al. 2022

Biomedicines

Self Cite

View full text Add to dashboard Cite

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

show abstract

“…Previous studies established that polymer nanoparticles designed for specific purpose are efficient in siRNA, microRNAs and drugs delivery ( Maestro et al, 2021 ). Lipid nanoparticles (LNPs) are formed by amphiphilic lipids, suitable as vehicles for nucleic acid delivery.…”

Section: Gene Therapy Of Refractory Hypercholesterolemiamentioning

confidence: 99%

The Progression of Treatment for Refractory Hypercholesterolemia: Focus on the Prospect of Gene Therapy

2022

Front. Genet.

View full text Add to dashboard Cite

Refractory hypercholesterolemia (RH), including homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia, is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) despite existing cholesterol-lowering methods at maximal tolerable doses. Patients with RH have early onset and higher risk of atherosclerotic cardiovascular disease (ASCVD) under insufficient treatment. Therefore, it is urgent to seek new therapies to maintain the blood lipids in refractory hyperlipidemia at normal levels. Currently, new cholesterol-lowering strategies are on the market, not only at the protein level [i.e., bempedoic acid (inhibiting ATP-citrate lyase), alirocumab and evolocumab (monoclonal antibodies against PCSK9), evinacumab (monoclonal antibody against ANGPTL3)] but also at the transcript level [i.e., mipomersen (antisense oligonucleotide inhibiting ApoB), inclisiran (siRNA targeting PCSK9)], providing more options for RH patients to achieve their lipid-lowering targets. More RNA-based therapies targeting RH-related genes have been designed for the treatment. However, for a proportion of patients, especially those with LDLR deficiency, the available treatments are still insufficient. More recently, emerging genome engineering based on CRISPR/Cas9 techniques, and advanced delivery technologies such as lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, lipid nanoparticles, and exosomes are being rapidly developed and implemented as novel therapies for RH. Gene therapy targeting RH-related genes has been successfully conducted in cells, mice, and non-human primates with high efficacy in lipid lowering and good tolerability. Especially the new generation of genome editing technique, base editing, performed in vivo with ideal lipid-lowering effect and limited occurrence of unwanted results. Excitingly, a phase I/II clinical study of LDLR gene replacement has been recently completed in RH patients, likely to be employed in clinical practice in the future. Furthermore, new targets for cholesterol reduction such as REV-ERB, G protein-coupled receptor, Ubiquitin specific peptidase 20 are continually being developed. This narrative review updates recent advances in treatment for RH, summarizes related clinical trials and preclinical studies, especially on the prospect of gene therapy.

show abstract

Novel vectors and approaches for gene therapy in liver diseases

Cited by 78 publications

References 147 publications

MiR‐26a‐tetrahedral framework nucleic acids mediated osteogenesis of adipose‐derived mesenchymal stem cells

MiR‐26a‐tetrahedral framework nucleic acids mediated osteogenesis of adipose‐derived mesenchymal stem cells

Gene Therapy for Acquired and Genetic Cholestasis

The Progression of Treatment for Refractory Hypercholesterolemia: Focus on the Prospect of Gene Therapy

Contact Info

Product

Resources

About