Optimization strategies and advances in the research and development of AAV‐based gene therapy to deliver large transgenes

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(3)

Опубликована: Март 1, 2024

Adeno-associated virus (AAV)-based therapies are recognized as one of the most potent next-generation treatments for inherited and genetic diseases. However, several biological technological aspects AAV vectors remain a critical issue their widespread clinical application. Among them, limited capacity genome significantly hinders development AAV-based gene therapy. In this context, genetically modified transgenes compatible with opening up new opportunities unlimited many disorders. Recent advances in de novo protein design remodelling paving way new, more efficient targeted therapeutics. Using computational tools, expression cassette transgenic DNA can be split, miniaturized, shuffled or created from scratch to mediate transfer into cells. review, we highlight recent therapy focus on its use translational research. We summarize research therapy, an emphasis large (>4.8 kb) optimizing strategies applied by biomedical companies pipeline. critically discuss prospects treatment some emerging challenges. anticipate that continued novel tools will lead rapid basic studies.

Язык: Английский

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Advances in Gene Therapy for Rare Diseases: Targeting Functional Haploinsufficiency Through AAV and mRNA Approaches

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 578 - 578

Опубликована: Янв. 11, 2025

Most rare diseases (RDs) encompass a diverse group of inherited disorders that affect millions people worldwide. A significant proportion these are driven by functional haploinsufficiency, which is caused pathogenic genetic variants. Currently, most treatments for RDs limited to symptom management, emphasizing the need therapies directly address deficiencies. Recent advancements in gene therapy, particularly with adeno-associated viruses (AAVs) and lipid nanoparticle-encapsulated messenger RNA (mRNA), have introduced promising therapeutic approaches. AAV vectors offer durable expression, extensive tissue tropism, safety profile makes them leading choice delivery; however, limitations remain, including packaging size immune response. In contrast, mRNA therapeutics, formulated LNPs, facilitate transient protein expression without risk genomic integration, supporting repeated dosing pharmacokinetic control, though less long-term than AAVs. This review analyzes latest developments technologies monogenic disorders, focusing on preclinical clinical outcomes, vector design, delivery challenges. We also key regulatory immunological considerations impacting success. Together, technology underscore new era RD treatment, providing innovative tools target root expanding approaches patients who currently face medical options.

Язык: Английский

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The Evolving Landscape of NF Gene Therapy: Hurdles and Opportunities

Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(1), С. 102475 - 102475

Опубликована: Фев. 4, 2025

Neurofibromatosis type 1 (NF1)- and NF2-related schwannomatosis are rare autosomal dominant monogenic disorders characterized by a predisposition for nerve-associated tumors. Current treatments focus on symptomatic management, but advancements in the gene therapy field present unique opportunities to treat genetic underpinnings develop curative therapies NF. Approaches such as nonsense suppression agents oligonucleotide becoming more mature have emerging preclinical data context of Furthermore, there has been progress developing vectors that can be delivered locally into tumors ablate or shrink their size. While still nascent research area, addition repair strategies hold tremendous promise prevention treatment NF-related These technologies will also require parallel development delivery able target Schwann cells from which most commonly arise. This review seeks contextualize these hurdles remain clinical adoption.

Язык: Английский

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Recent Advances in Gene Therapy for Hemophilia: Projecting the Perspectives

Biomolecules, Год журнала: 2024, Номер 14(7), С. 854 - 854

Опубликована: Июль 15, 2024

One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result mutation in

Язык: Английский

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Chromatography in Downstream Processing of Recombinant Adeno‐Associated Viruses: A Review of Current and Future Practises

Biotechnology and Bioengineering, Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

ABSTRACT Recombinant adeno‐associated virus (rAAV) has emerged as an attractive gene delivery vector platform to treat both rare and pervasive diseases. With more rAAV‐based therapies entering late‐stage clinical trials commercialization, there is increasing pressure on the rAAV manufacturing process accelerate drug development, account for larger trials, commercially provide high doses. Still, many of pre‐clinical processes are tied outdated technologies, which results in substantial production expenses. Those face challenges including low productivity difficult scalability, limits its ability required dosages turn influences accessibility drug. And upstream efforts expected increase productivities, downstream part needs adapt with scalable efficient technologies. In this review, traditional novel technologies presented discussed. Traditional based density gradient ultracentrifugation have been shown effectively purify rAAVs yields purities. However, those lack scalability efficiency, why column‐chromatography alternative show potential integration continuous processes, following principle next‐generation manufacturing.

Язык: Английский

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Gene Therapy with Gene Delivery Systems and Therapeutic Strategies: A New Frontier in Cancer Treatment

Journal of Drug Delivery Science and Technology, Год журнала: 2025, Номер unknown, С. 106798 - 106798

Опубликована: Март 1, 2025

Язык: Английский

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Delivery of DNA-Based Therapeutics for Treatment of Chronic Diseases

Pharmaceutics, Год журнала: 2024, Номер 16(4), С. 535 - 535

Опубликована: Апрель 13, 2024

Gene therapy and its role in the medical field have evolved drastically recent decades. Studies aim to define DNA-based medicine as well encourage innovation further development of novel approaches. has been established an alternative approach treat a variety diseases. Its range mechanistic applicability is wide; gene capacity address symptoms disease, body’s ability fight some cases cure making it more attractive intervention than traditional approaches treatment (i.e., surgery). Such versatility also suggests potential greater number indications conventional treatments. Many therapies shown promise clinical trials, several approved for use humans. Whereas current regimens chronic disease often require frequent dosing, can produce robust durable expression therapeutic genes with fewer This benefit encourages application manage diseases, area where improving efficiency treatments urgent. Here, we provide overview two their delivery methods: adeno associated virus (AAV)-based plasmid DNA (pDNA)-based therapy. We will focus on how these already utilized improve literature supports expansion additional future.

Язык: Английский

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Serotype-agnostic affinity purification of adeno-associated virus (AAV) via peptide-functionalized chromatographic resins

Journal of Chromatography A, Год журнала: 2024, Номер 1734, С. 465320 - 465320

Опубликована: Авг. 28, 2024

Язык: Английский

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Implementation of the quality-by-design concept for an adeno-associated viral vector-based gene therapy

Biological Products Prevention Diagnosis Treatment, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

INTRODUCTION. Currently, manufacturers of adeno-associated virus (AAV)-based gene therapy products are facing a number systemic problems stemming from the difficulties in assessing quality medicinal due to insufficient scientific data, limited experience, and imperfect regulatory requirements. However, risk-based approach critical attributes (CQAs) within framework Quality by Design (QbD) can ensure improved efficiency development production advanced products. AIM. This study aimed identify QbD-based CQAs associated specifications for AAV-based Duchenne muscular dystrophy. DISCUSSION. involved an analysis approaches AAV technologies. The authors substantiated list main characteristics collated available data on their impact patients terms efficacy safety and, particular, immune response treatment. Following risk assessment, identified AAVs. When developing process, determined CQAs, including viral infectious titres, presence replication-competent AAVs, percentage empty capsids, residual impurities (proteins, plasmid DNA, host-cell DNA). A comprehensive assessment was conducted determine target product profile listed developed basic requirements applicable analytical procedures, established CQA product. CONCLUSIONS. use QbD principles is important step identification during methodology facilitates drafting new standards evaluation helps with commercial-scale manufacturing such

Язык: Английский

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Structural studies of Parvoviridae capsid assembly and evolution: implications for novel AAV vector design

Frontiers in Artificial Intelligence, Год журнала: 2025, Номер 8

Опубликована: Апрель 2, 2025

Adeno-associated virus (AAV) vectors have emerged as powerful tools in gene therapy, potentially treating various genetic disorders. Engineering the AAV capsids through computational methods enables customization of these to enhance their effectiveness and safety. This engineering allows for development therapies that are not only more efficient but also personalized unique profiles. When developing, it is essential understand structural biology vast techniques used guide vector designs. review covers fundamental Parvoviridae capsids, focusing on modern study techniques, including (a) Cryo-electron microscopy X-ray Crystallography studies (b) Comparative analysis capsid structures across different species. Along with structure evolution provided significant insights into design novel which include Structure-guided improved properties, Directed Evolution specific applications, (c) Computational prediction capsid-receptor interactions. Further discussion addressed ongoing challenges proposed future directions exploring enhanced tools, such artificial intelligence/machine learning deep learning.

Язык: Английский

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