AAV- based vector improvements unrelated to capsid protein modification

Shitik, Ekaterina M.; Shalik, Igor K.; Yudkin, Dmitry V.

doi:10.3389/fmed.2023.1106085

Cited by 6 publications

(6 citation statements)

References 111 publications

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“…15 Despite the aforementioned advantages, scAAVs have a decreased capacity to ∼2.5 kb compared to conventional single-stranded AAV that drastically limits their wide application. 65,69 Other components of AAV expression cassettes such as PRE and poly(A) signals are also objects of optimization to expand the capacity of AAV vectors. The SV40 virus, human growth hormone and bovine growth hormone polyadenylation signals are the most commonly used in AAV expression cassettes.…”

Section: Modifications Of Genetic Regulatory Elements Of Aav Expressi...mentioning

confidence: 99%

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

Kolesnik,

Nurtdinov,

Oloruntimehin

et al. 2024

Clinical & Translational Med

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

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Section: Modifications Of Genetic Regulatory Elements Of Aav Expressi...mentioning

confidence: 99%

“…Despite the aforementioned advantages, scAAVs have a decreased capacity to ∼2.5 kb compared to conventional single‐stranded AAV that drastically limits their wide application 65,69 …”

Section: Modifications Of Genetic Regulatory Elements Of Aav Expressi...mentioning

confidence: 99%

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

Kolesnik,

Nurtdinov,

Oloruntimehin

et al. 2024

Clinical & Translational Med

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“…With immunity proven to play a fundamental role in efficiency of treatment, methods to improve AAV technology to avoid such responses are currently being investigated [ 47 , 48 ]. Strategies addressing immunity, as well as other limitations of AAV, include, but are not limited to, optimizing dosing regimen [ 49 ], further engineering of AAV capsids [ 50 , 51 ], and vector development such as self-complementary AAVs (scAAVs) [ 51 , 52 , 53 , 54 ].…”

Section: Adeno-associated Virus-based Gene Therapymentioning

confidence: 99%

Delivery of DNA-Based Therapeutics for Treatment of Chronic Diseases

Sussman,

Liberatore,

Drozdz

2024

Pharmaceutics

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

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“…Features within both the AAV genome and capsids contribute to AAV toxicity. Certain cis-regulatory elements found in commonly used non-tissue specific promoters, such as cytomegalovirus (CMV) and chicken beta actin (CAG) promoters, p53 binding elements within the ITRs, and ITR promoter activity have been linked to toxicity [87][88][89][90]. rAAV integration-mediated oncogenicity has been controversial, with contradicting information.…”

Section: Toxicity Of Raavmentioning

confidence: 99%

AAV Immunotoxicity: Implications in Anti-HBV Gene Therapy

Jacobs,

Dogbey,

Mnyandu

et al. 2023

Microorganisms

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Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent years and research has made exciting leaps. Initial studies, mainly using mouse models, showed that rAAVs are non-toxic and induce minimal immune responses. However, several later studies demonstrated rAAV toxicity, which is inextricably associated with immunogenicity. This is a major setback for the progression of rAAV-based therapies toward clinical application. Research aimed at understanding the mechanisms behind rAAV immunity and toxicity has contributed significantly to the inception of approaches to overcoming these challenges. The target tissue, the features of the vector, and the vector dose are some of the determinants of AAV toxicity, with the latter being associated with the most severe adverse events. This review discusses our current understanding of rAAV immunogenicity, toxicity, and approaches to overcoming these hurdles. How this information and current knowledge about HBV biology and immunity can be harnessed in the efforts to design safe and effective anti-HBV rAAVs is discussed.

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AAV- based vector improvements unrelated to capsid protein modification

Cited by 6 publications

References 111 publications

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

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

Delivery of DNA-Based Therapeutics for Treatment of Chronic Diseases

AAV Immunotoxicity: Implications in Anti-HBV Gene Therapy

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