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Currently, 33 gene‐therapy drugs/products have been approved in the clinic. Over 3000 completed and ongoing clinical gene therapy trials have been reported worldwide. The development/maturation of tools for gene manipulation and gene delivery, as well as molecular advances in the diagnosis of genetic diseases, have played a central role in gene the...
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Nanomaterials are currently being developed for the specific cell/tissue/organ delivery of genetic material. Nanomaterials are considered as non-viral vectors for gene therapy use. However, there are several requirements for developing a device small enough to become an efficient gene-delivery tool. Considering that the non-viral vectors tested so...
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... HMGA2 siRNA can reduce cell viability and migration, as well as increase apoptosis of PC3 cells (Khajouee et al. 2022). Currently, the use of HMGA2siRNA has been proposed to improve proliferation and invasion ability of cancer (Liu et al. 2017); however, there remain many obstacles to the clinical translation of siRNAs, including low scalability, high cost, half-life, and short shelf life, which limit their large-scale use (Shahryari et al. 2021). Nano-technology and drug delivery approaches have a major part to play in treatment of BC (Liyanage et al. 2019;Garbayo et al. 2020). ...
High mobility group AT-hook 2 (HMGA2) is a member of the non-histone chromosomal high mobility group (HMG) protein family, which participate in embryonic development and other biological processes. HMGA2 overexpression is associated with breast cancer (BC) cell growth, proliferation, metastasis, and drug resistance. Furthermore, HMGA2 expression is positively associated with poor prognosis of patients with BC, and inhibiting HMGA2 signaling can stimulate BC cell progression and metastasis. In this review, we focus on HMGA2 expression changes in BC tissues and multiple BC cell lines. Wnt/β-catenin, STAT3, CNN6, and TRAIL-R2 proteins are upstream mediators of HMGA2 that can induce BC invasion and metastasis. Moreover, microRNAs (miRNAs) can suppress BC cell growth, invasion, and metastasis by inhibiting HMGA2 expression. Furthermore, long noncoding RNAs (LncRNAs) and circular RNAs (CircRNAs) mainly regulate HMGA2 mRNA and protein expression levels by sponging miRNAs, thereby promoting BC development. Additionally, certain small molecule inhibitors can suppress BC drug resistance by reducing HMGA2 expression. Finally, we summarize findings demonstrating that HMGA2 siRNA and HMGA2 siRNA-loaded nanoliposomes can suppress BC progression and metastasis.
... 112 One of the challenges in gene therapy is the lack of efficient carriers that can deliver nucleic acids to specific regions of target cells and release DNA/RNA rapidly. 113,114 Cationic polymers, such as polyethylenimine (PEI) and polyamidoamine (PAMAM), are generally nonimmunogenic and conveniently scalable for production, making them widely applicable in gene transfection. 115,116 However, their clinical application is limited due to their high cytotoxicity, nondegradability, and difficulty in rapid nucleic acid release. ...
Stimuli-responsive self-immolative polymers (SIPs) represent a unique class of polymers that can undergo controlled, sequential head-to-tail depolymerization upon specific stimuli. Since their inception, they have evolved over two decades to become one of the most attractive polymer types. With their characteristic feature of “one stimulus, multiple responses”, SIPs inherently possess the ability to serve as chemical amplifiers, which can amplify weak chemical or biological signals. This feature promises higher stimulus sensitivity, greater selectivity for specific microenvironments, and the potential to generate more persistent, extensive, and significant responses while consuming fewer stimuli sources. This Review summarizes the latest research advancements in stimuli-responsive SIPs for drug delivery and molecular imaging over the past five years. Regarding the structure of SIPs, we briefly overview the updates in self-immolation units, end-cap moieties, and sequence of SIPs. In terms of applications, we focus on the possible biological applications of SIPs in drug delivery for disease treatment and potential imaging methods. Finally, we provide a brief perspective of potential future directions for SIPs in these applications.
... Meanwhile, VP2 contains the entire sequence of VP3 and the VP1/VP2 common region. Recombinant AAV (rAAV), in which the rep/cap genes are replaced with a therapeutic gene, is used as a viral vector for in vivo human gene therapy because of its wide tissue tropism, low pathogenicity, and ability to sustain the long-term gene expression of a transgene [2,[6][7][8]. Although several products have already been approved in the US and a large number of clinical trials are ongoing [6,9], the detailed structural mechanism underlying the biological function of rAAV capsids remains elusive. ...
... Recombinant AAV (rAAV), in which the rep/cap genes are replaced with a therapeutic gene, is used as a viral vector for in vivo human gene therapy because of its wide tissue tropism, low pathogenicity, and ability to sustain the long-term gene expression of a transgene [2,[6][7][8]. Although several products have already been approved in the US and a large number of clinical trials are ongoing [6,9], the detailed structural mechanism underlying the biological function of rAAV capsids remains elusive. To develop rAAV capsid engineering and quality control, there is a need to clarify the mechanisms by which VP1 and VP2 N-terminal regions, which are supposed to be located conformational differences in each protein state. ...
The higher-order structure (HOS) is a critical quality attribute of recombinant adeno-associated viruses (rAAVs). Evaluating the HOS of the entire rAAV capsid is challenging because of the flexibility and/or less folded nature of the VP1 unique (VP1u) and VP1/VP2 common regions, which are structural features essential for these regions to exert their functions following viral infection. In this study, hydrogen/deuterium exchange mass spectrometry (HDX-MS) was used for the structural analysis of full and empty rAAV8 capsids. We obtained 486 peptides representing 85% sequence coverage. Surprisingly, the VP1u region showed rapid deuterium uptake even though this region contains the phospholipase A2 domain composed primarily of α-helices. The comparison of deuterium uptake between full and empty capsids showed significant protection from hydrogen/deuterium exchange in the full capsid at the channel structure of the 5-fold symmetry axis. This corresponds to cryo-electron microscopy studies in which the extended densities were observed only in the full capsid. In addition, deuterium uptake was reduced in the VP1u region of the full capsid, suggesting the folding and/or interaction of this region with the encapsidated genome. This study demonstrated HDX-MS as a powerful method for probing the structure of the entire rAAV capsid.
... Utilizing CQDs as nonviral gene vectors can potentially address some constraints. Their extremely small size allows for easy absorption by cells, while their surface modification and ability to emit light enable the monitoring of their delivery and customization for particular targeting to desired cells (Shahryari et al., 2021). CQDs have shown reduced toxicity and immunogenicity in initial tests, as compared to other nanomaterials used as gene carriers (Hasanzadeh et al., 2021). ...
Gene therapy is a revolutionary technology in healthcare that provides novel therapeutic options and has immense potential in addressing genetic illnesses, malignancies, and viral infections. Nevertheless, other obstacles still need to be addressed regarding safety, ethical implications, and technological enhancement. Nanotechnology and gene therapy fields have shown significant promise in transforming medical treatments by improving accuracy, effectiveness, and personalization. This review assesses the possible uses of gene therapy, its obstacles, and future research areas, specifically emphasizing the creative combination of gene therapy and nanotechnology. Nanotechnology is essential for gene delivery as it allows for the development of nano‐scale carriers, such as carbon quantum dots (CQDs), which may effectively transport therapeutic genes into specific cells. CQDs exhibit distinctive physicochemical characteristics such as small size, excellent stability, and minimal toxicity, which render them highly favorable for gene therapy applications. The objective of this study is to review and describe the current advancements in the utilization of CQDs for gene delivery. Additionally, it intends to assess existing research, explore novel applications, and identify future opportunities and obstacles. This study offers a thorough summary of the current state and future possibilities of using CQDs for gene delivery. Combining recent research findings highlights the potential of CQDs to revolutionize gene therapy and its delivery methods.
... However, major adverse reactions (e.g., anaphylaxis and Bell's palsy), as well as common side effects (e.g., fever, fatigue, headache, and swelling at the injection site), are associated with mRNA vaccines, which may be related to LNPs [3,4]. As alternative strategies to these vector applications, the chemical modification and local application of naked nucleic acids are expected for increased safety, some of which (e.g., Givlaari ® as siRNA and Collategene ® as pDNA) have already been approved for clinical use [5]. Givlaari ® is effectively delivered to liver parenchymal cells after subcutaneous injection via N-acetylgalactosamine conjugation, escaping nuclease degradation in the blood by 2 -O-methyl, 2 -deoxy-2 -fluoro, and phosphorothioate modification. ...
A number of functional nucleic acids, including plasmid DNA (pDNA) and small interfering RNA (siRNA), have been attracting increasing attention as new therapeutic modalities worldwide. Dry pDNA and siRNA powder formulations for inhalation are considered practical in clinical applications for respiratory diseases. However, physical stresses in the powder-forming process may destabilize nucleic acids, particularly when vectors with stabilizing effects are not used. We herein compare the stability of naked pDNA and siRNA through various physical treatments and two powder-forming processes. The structural and functional integrities of pDNA were markedly reduced via sonication, heating, and atomization, whereas those of siRNA were preserved throughout all of the physical treatments investigated. Spray-dried and spray-freeze-dried powders of siRNA maintained their structural and functional integrities, whereas those of pDNA did not. These results
demonstrate that siRNA is more suitable for powder formation in the naked state than pDNA due to its higher stability under physical treatments. Furthermore, a spray-freeze-dried powder with a high content of naked siRNA (12% of the powder) was successfully produced that preserved its structural and functional integrities, achieving high aerosol performance with a fine particle fraction of approximately 40%.
... In the 20 years since the first approved genetic therapy, 33 gene therapies have been approved, and there are thousands of on-going clinical trials exploring novel genetic approaches across a wide variety of diseases (Shahryari et al., 2021). However, cardiovascular disease is still relatively under-represented in on-going clinical trials of gene therapies. ...
Skeletal myopathies and ataxias with secondary cardiac involvement are complex, progressive and debilitating conditions. As life expectancy increases across these conditions, cardiac involvement often becomes more prominent. This highlights the need for targeted therapies that address these evolving cardiac pathologies. Musculopathies by and large lack cures that directly target the genetic basis of the diseases; however, as our understanding of the genetic causes of these conditions has evolved, it has become tractable to develop targeted therapies using biologics, to design precision approaches to target the primary genetic causes of these varied diseases. Using the examples of Duchenne muscular dystrophy, Friedreich ataxia and Pompe disease, we discuss how the genetic causes of such diseases derail diverse homeostatic, energetic and signalling pathways, which span multiple cellular systems in varied tissues across the body. We outline existing therapeutics and treatments in the context of emerging novel genetic approaches. We discuss the hurdles that the field must overcome to deliver targeted therapies across the many tissue types affected in primary myopathies.
... In general, there are some safety concerns about viral usage, i.e., the ability of the viral genome to be incorporated into the receiver species [65] and the possibility that viral shedding occurs in bodily fluids [66] and poses a public health risk. Using nonpathogenic viral vectors with stable genomes or the engineering of nonviral carriers allows for circumventing this issue and mitigating potential safety risks. ...
Feline population control remains a concern as to whether it is intended for the short- or long-term. Induced sterilization of felids is critical in the case of feral, free-roaming cats, or the management of wild populations in Zoos or sanctuaries. This narrative review explores the shifting paradigm in induced sterilization methods, driven by the development of gene editing approaches recently applied to control felid reproductive activity. Although gene therapy approaches have gained attention as alternatives to more traditional methods, their clinical applications remain in the realm of thought. The objective of this study was to provide a comprehensive overview of the current state and most recent advances in gene-based contraception options, consolidate current research and evidence, and share some considerations on its potential effectiveness, advantages or limitations, and implications for animal welfare and population control strategies. Gene-based contraception therapy tested in felines, targeting the AMH pathway, was unable to suppress the estrous cycle and follicular development. However, at an experimental level, preliminary results hint at the need to change towards different molecular targets. Moreover, their side effects remain largely unknown, and several questions remain unanswered, such as the regularity of treatment applications or cost.
... One advantage of TALENs for researchers is that all the RVDs and their recognized sequences are open resources, while ZFNs are only available from Sangamo Therapeutics, Richmond, CA, USA. So far, there have been several TALEN-based gene-and cell-therapies under clinical trials [68,69]. ...
Applying programmable nucleases in gene editing has greatly shaped current research in basic biology and clinical translation. Gene editing in human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), is highly relevant to clinical cell therapy and thus should be examined with particular caution. First, since all mutations in PSCs will be carried to all their progenies, off-target edits of editors will be amplified. Second, due to the hypersensitivity of PSCs to DNA damage, double-strand breaks (DSBs) made by gene editing could lead to low editing efficiency and the enrichment of cell populations with defective genomic safeguards. In this regard, DSB-independent gene editing tools, such as base editors and prime editors, are favored due to their nature to avoid these consequences. With more understanding of the microbial world, new systems, such as Cas-related nucleases, transposons, and recombinases, are also expanding the toolbox for gene editing. In this review, we discuss current applications of programmable nucleases in PSCs for gene editing, the efforts researchers have made to optimize these systems, as well as new tools that can be potentially employed for differentiation modeling and therapeutic applications.
... Another potential use of siRNA relies on immunotherapy, as these molecules are capable of stimulating the innate immune system and modulating the tumor microenvironment (TME) [6,7]. However, the low scalability and high costs of these treatments have limited their large-scale use [8]. Indeed, siRNA molecules are very fragile with extremely limited shelf-life, and also half-life once administered [9,10]. ...
RNA-based therapies, and siRNAs in particular, have attractive therapeutic potential for cancer treatment due to their ability to silence genes that are imperative for tumor progression. To be effective and solve issues related to their poor half-life and poor pharmacokinetic properties, siRNA require adequate drug delivery systems that protect them from degradation and allow intracellular delivery. Among the various delivery vehicles available, lipid nanoparticles have emerged as the leading choice. These nanoparticles consist of cholesterol, phospholipids, PEG-lipids and most importantly ionizable cationic lipids. These ionizable lipids enable the binding of negatively charged siRNA, resulting in the formation of stable and neutral lipid nanoparticles with exceptionally high encapsulation efficiency. Lipid nanoparticles have demonstrated their effectiveness and versatility in delivering not only siRNAs but also multiple RNA molecules, contributing to their remarkable success. Furthermore, the advancement of efficient manufacturing techniques such as microfluidics, enables the rapid mixing of two miscible solvents without the need for shear forces. This facilitates the reproducible production of lipid nanoparticles and holds enormous potential for scalability. This is shown by the increasing number of preclinical and clinical trials evaluating the potential use of siRNA-LNPs for the treatment of solid and hematological tumors as well as in cancer immunotherapy. In this review, we provide an overview of the progress made on siRNA-LNP development for cancer treatment and outline the current preclinical and clinical landscape in this area. Finally, the translational challenges required to bring siRNA-LNPs further into the clinic are also discussed.
... Therapeutic plasmid delivery as a novel treatment modality has its roots in the ever-growing understanding of the human genome and the underlying genetic aberrations now associated with previously incurable diseases, such as Parkinson's and Alzheimer's [180]. The ability to alter the root cause of a disease to modify its activity or progression is an attractive therapeutic goal, evidenced by the over 3000 completed or ongoing gene therapy trials reported worldwide [181]. The difficulty of developing a successful therapy appropriate for treatment may, therefore, be highlighted by the comparatively small number of approved gene-therapy drugs/ products, which totalled 33 in mid-2021 [181]. ...
... The ability to alter the root cause of a disease to modify its activity or progression is an attractive therapeutic goal, evidenced by the over 3000 completed or ongoing gene therapy trials reported worldwide [181]. The difficulty of developing a successful therapy appropriate for treatment may, therefore, be highlighted by the comparatively small number of approved gene-therapy drugs/ products, which totalled 33 in mid-2021 [181]. Commonly cited challenges to successful translation to the clinic include their anionic charge, susceptibility to enzymatic degradation in the bloodstream and tissues, their inherent immunogenicity and their inhibited capacity to be delivered to the correct cell population [182]. ...
Ultrasound has long been identified as a promising, non-invasive modality for improving ocular drug delivery across a range of indications. Yet, with 20 years of learnings behind us, clinical translation remains limited. To help address this, and in accordance with PRISMA guidelines, the various mechanisms of ultrasound-mediated ocular drug delivery have been appraised, ranging from first principles to emergent applications spanning both ex vivo and in vivo models. The heterogeneity of study methods precluded meta-analysis, however an extensive characterisation of the included studies allowed for semi-quantitative and qualitative assessments. Methods: In this review, we reflected on study quality of reporting, and risk of bias (RoB) using the latest Animal Research: Reporting of In Vivo Experiments (ARRIVE 2.0) guidelines, alongside the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) RoB tools. Literature studies from 2002 to 2022 were initially characterised according to methods of ultrasound application, ultrasound parameters applied, animal models employed, as well as safety and efficacy assessments. This exercise contributed to developing a comprehensive understanding of the current state of play within ultrasound-mediated ocular drug delivery. The results were then synthesised and processed into a guide to aid future study design, with the goal of improving the reliability of data, and to support efficient and timely translation to the clinic. Results: Key attributes identified as hindering translation included: poor reporting quality and high RoB, skewed use of animals unrepresentative of the human eye, and the over reliance of reductionist safety assessments. Ex vivo modelling studies were often unable to have comprehensive safety assessments performed on them, which are imperative to determining treatment safety, and represent a prerequisite for clinical translation. Conclusion: With the use of our synthesised guide, and a thorough understanding of the underlying physicochemical interactions between ultrasound and ocular biology provided herein, this review offers a firm foundation on which future studies should ideally be built, such that ultrasound-mediated ocular drug delivery can be translated from concept to the coalface where it can provide immense clinical benefit.
