Design of AAV Vectors for Delivery of Large or Multiple Transgenes

Zhao, Jianwei; Duan, Dongsheng; Lai, Yi

doi:10.1007/978-1-4939-9139-6_2

Cited by 43 publications

(24 citation statements)

References 77 publications

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“…Additional synthetic AAV subtypes have been derived/engineered in the laboratory to optimize these features for gene transfer (Kotterman and Schaffer, 2014 ). Impinging considerably upon its tractability, the packaging capacity of AAV is limited to ≈4.7 kb, which is halved in the more rapidly expressing self-complementary AAV (for simplicity, we refer to single-stranded and self-complementary AAV as one), although DNA delivery across separate AAV particles is possible (Patel et al, 2019 ). In most cases, AAV vectors induce limited immunogenicity in naïve hosts (Ronzitti et al, 2020 ), and have a good safety record, although there may be toxicity issues when administered at high doses (Hinderer et al, 2018 ).…”

Section: Gene Therapy Virusesmentioning

confidence: 99%

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Tosolini

Sleigh

2020

Front. Mol. Neurosci.

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Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia. This route is minimally invasive and therefore clinically relevant for gene therapy targeting to peripheral nerve soma. For successful transgene expression, viruses administered into muscle must undergo a series of processes, including host cell interaction and internalization, intracellular sorting, long-range retrograde axonal transport, endosomal liberation, and nuclear import. In this review article, we outline key characteristics of major gene therapy viruses—adenovirus, adeno-associated virus (AAV), and lentivirus—and summarize the mechanisms regulating important steps in the virus journey from binding at peripheral nerve terminals to nuclear delivery. Additionally, we describe how neuropathology can negatively influence these pathways, and conclude by discussing opportunities to optimize the intramuscular administration route to maximize gene delivery and thus therapeutic potential.

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Section: Gene Therapy Virusesmentioning

confidence: 99%

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Tosolini

Sleigh

2020

Front. Mol. Neurosci.

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“…This characteristic raises concern about insertional mutagenesis. AAV also possesses a small transgene cargo capacity (~4.5 kb) 8,9 and cannot deliver large genes such as huntingtin (9.4 kb) or dystrophin (11 kb) or multiple genes. These aspects suggest that an in vivo gene delivery vector with a high safety profile and large transgene cargo capacity but no ability to randomly integrate into the host genome is more desirable, and such a vector could provide better opportunities for in vivo gene therapy.…”

Section: Introductionmentioning

confidence: 99%

No more helper adenovirus: production of gutless adenovirus (GLAd) free of adenovirus and replication-competent adenovirus (RCA) contaminants

et al. 2019

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Gene therapy is emerging as an effective treatment option for various inherited genetic diseases. Gutless adenovirus (GLAd), also known as helper-dependent adenovirus (HDAd), has many notable characteristics as a gene delivery vector for this particular type of gene therapy, including broad tropism, high infectivity, a large transgene cargo capacity, and an absence of integration into the host genome. Additionally, GLAd ensures long-term transgene expression in host organisms owing to its minimal immunogenicity, since it was constructed following the deletion of all the genes from an adenovirus. However, the clinical use of GLAd for the treatment of inherited genetic diseases has been hampered by unavoidable contamination of the highly immunogenic adenovirus used as a helper for GLAd production. Here, we report the production of GLAd in the absence of a helper adenovirus, which was achieved with a helper plasmid instead. Utilizing this helper plasmid, we successfully produced large quantities of recombinant GLAd. Importantly, our helper plasmid-based system exclusively produced recombinant GLAd with no generation of helper plasmid-originating adenovirus and replication-competent adenovirus (RCA). The recombinant GLAd that was produced efficiently delivered transgenes regardless of their size and exhibited therapeutic potential for Huntington’s disease (HD) and Duchenne muscular dystrophy (DMD). Our data indicate that our helper plasmid-based GLAd production system could become a new platform for GLAd-based gene therapy.

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“…To overcome the packaging capacity limitation of AAV, a split AAV gene delivery approach can be implemented, wherein a large transgene is split across multiple separate AAV vectors (Patel et al, 2019a). As a means of screening for AAV serotypes that display airway tropism and permit efficient gene delivery to the human lung parenchyma, lung bud organoids-a model of lung parenchyma derived from human embryonic stem cells-have been utilized (Meyer-Berg et al, 2020).…”

Section: Adeno-associated Virusmentioning

confidence: 99%

Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies

et al. 2021

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Prognosis of patients with cystic fibrosis (CF) varies extensively despite recent advances in targeted therapies that improve CF transmembrane conductance regulator (CFTR) function. Despite being a multi-organ disease, extensive lung tissue destruction remains the major cause of morbidity and mortality. Progress towards a curative treatment strategy that implements a CFTR gene addition-technology to the patients’ lungs has been slow and not yet developed beyond clinical trials. Improved delivery vectors are needed to overcome the body’s defense system and ensure an efficient and consistent clinical response before gene therapy is suitable for clinical care. Cell-based therapy–which relies on functional modification of allogenic or autologous cells ex vivo, prior to transplantation into the patient–is now a therapeutic reality for various diseases. For CF, pioneering research has demonstrated proof-of-principle for allogenic transplantation of cultured human airway stem cells into mouse airways. However, applying a cell-based therapy to the human airways has distinct challenges. We review CF gene therapies using viral and non-viral delivery strategies and discuss current advances towards autologous cell-based therapies. Progress towards identification, correction, and expansion of a suitable regenerative cell, as well as refinement of pre-cell transplant lung conditioning protocols is discussed.

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Design of AAV Vectors for Delivery of Large or Multiple Transgenes

Cited by 43 publications

References 77 publications

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

No more helper adenovirus: production of gutless adenovirus (GLAd) free of adenovirus and replication-competent adenovirus (RCA) contaminants

Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies

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