Liver targeted gene therapy: Insights into emerging therapies

Moscoso, Carlos G.; Steer, Clifford J.

doi:10.1016/j.ddtec.2020.11.001

Cited by 6 publications

(3 citation statements)

References 88 publications

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“…34 Adenoviral [Coxsackievirus and adenovirus receptor (CAR)] and integrin receptors (αvβ3 and αvβ5) are naturally found on the surface of most human cells, which implies not only increased transduction efficiency but also increased levels of transgene expression. 35,36 However, AdV are also the viral vectors with the highest number of identified human serotypes (∼57) thus facilitating a pre-existing immunity. 34 This inherent immunogenicity elicited by AdVs poses restrictions on repeat administration in a single patient.…”

Section: Viral Gene Delivery Methodsmentioning

confidence: 99%

An Overview of Gene Editing Modalities and Related Non-clinical Testing Considerations

et al. 2023

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Gene therapy has become an important modality for a wide range of therapeutic indications with a rapid increase in the number of therapeutic candidates being developed in this field. Understanding the molecular biology underlying the gene therapy is often critical to develop appropriate safety assessment strategies. We aimed to discuss some of the commonly used gene therapy modalities and common preclinical toxicology testing considerations when developing gene therapies. Non-viral gene delivery methods such as electroporation, microinjection, peptide nanoparticles and lipid nanoparticles are deployed as innovative molecular molecular construct which are included in the design of novel gene therapies and the associated molecular biology mechanisms have become relevant knowledge to non-clinical toxicology. Viral gene delivery methodologies including Adenovirus vectors, Adeno-Associated virus vectors and Lentivirus gene therapy vectors have also advanced considerably across numerous therapeutic areas, raising unique non-clinical toxicology and immunological considerations. General toxicology, biodistribution and tumorigenicity are the pillars of non-clinical safety testing in gene therapies. Evaluating the tumorigenicity potential of a gene editing therapy often leverages molecular pathology while some translational challenges remain. Toxicology study design is entering a new era where science-driven customized approaches and program specific considerations have become the norm.

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Section: Viral Gene Delivery Methodsmentioning

confidence: 99%

An Overview of Gene Editing Modalities and Related Non-clinical Testing Considerations

et al. 2023

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“…For example, an optimized AAV was recently used in a study to deliver CRISPR to the liver of a mouse, demonstrating high specificity. AAVs have already found applications in clinical trials for conditions such as inherited retinal diseases, spinal muscular atrophy, and hemophilia ( Moscoso and Steer, 2019 ).…”

Section: Advantages and Limitations Of Gene Therapy In The Context Of...mentioning

confidence: 99%

Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update

Moaveni,

Amiri,

Shademan

et al. 2024

Front. Mol. Biosci.

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Pediatric cancers represent a tragic but also promising area for gene therapy. Although conventional treatments have improved survival rates, there is still a need for targeted and less toxic interventions. This article critically analyzes recent advances in gene therapy for pediatric malignancies and discusses the challenges that remain. We explore the innovative vectors and delivery systems that have emerged, such as adeno-associated viruses and non-viral platforms, which show promise in addressing the unique pathophysiology of pediatric tumors. Specifically, we examine the field of chimeric antigen receptor (CAR) T-cell therapies and their adaptation for solid tumors, which historically have been more challenging to treat than hematologic malignancies. We also discuss the genetic and epigenetic complexities inherent to pediatric cancers, such as tumor heterogeneity and the dynamic tumor microenvironment, which pose significant hurdles for gene therapy. Ethical considerations specific to pediatric populations, including consent and long-term follow-up, are also analyzed. Additionally, we scrutinize the translation of research from preclinical models that often fail to mimic pediatric cancer biology to the regulatory landscapes that can either support or hinder innovation. In summary, this article provides an up-to-date overview of gene therapy in pediatric oncology, highlighting both the rapid scientific progress and the substantial obstacles that need to be addressed. Through this lens, we propose a roadmap for future research that prioritizes the safety, efficacy, and complex ethical considerations involved in treating pediatric patients. Our ultimate goal is to move from incremental advancements to transformative therapies.

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“…The third strand, commonly known as Triplex Forming Oligonucleotide (TFO), targets the polypurine part of double‐stranded DNA forming two additional H‐bonds in parallel or antiparallel pattern relative to the polypurine strand through so‐called Hoogsteen or reverse Hoogsteen base pairing, respectively. Inhibition of gene expression using sequence‐specific TFO strategy offers a direct promising therapy on the DNA level to treat some gene‐related diseases such as cancer by suppressing oncogenes and proto‐oncogenes [2–4] . Targeted correction of gene mutation using TFO was also investigated to treat beta‐thalassemia and Duchenne muscular dystrophy diseases [5,6] …”

Section: Introductionmentioning

confidence: 99%

Enone as TFO Linker: Synthesis and Parallel DNA Triplex Stability Evaluation

et al. 2022

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Two new intercalated nucleic acid monomers, X and Y, possessing enone as linker have been synthesized. The monomers were incorporated into 14‐mer polypyrimidine strand to act as triplex‐forming oligonucleotide (TFO). The thermal stabilities of the formed parallel triplexes, parallel and antiparallel duplexes were evaluated to show high stability of its parallel triplexes at pH 5.0 and pH 7.2, while limited stability at pH 6.0 compared to unmodified triplex. The architectures of enone linker are shown to disturb the planarity of its parallel and antiparallel duplexes and consequently the π‐π stacking ability with the neighboring nucleobases. The data was confirmed by molecular dynamics simulation and binding energy calculations. Characteristic fluorescence spectra were also investigated to show the ability of X and Y containing TFO to discriminate parallel triplex from parallel and antiparallel duplex.

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Liver targeted gene therapy: Insights into emerging therapies

Cited by 6 publications

References 88 publications

An Overview of Gene Editing Modalities and Related Non-clinical Testing Considerations

An Overview of Gene Editing Modalities and Related Non-clinical Testing Considerations

Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update

Enone as TFO Linker: Synthesis and Parallel DNA Triplex Stability Evaluation

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