Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

Ronzitti, Giuseppe; Gross, David-Alexandre; Mingozzi, Federico

doi:10.3389/fimmu.2020.00670

Cited by 244 publications

(228 citation statements)

References 125 publications

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“…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 ). However, the AAV vector effect on brain homeostasis has not been completely addressed and is an important consideration (He et al, 2019 ).…”

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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“…In addition, pre-existing immunity to AAV capsid proteins occurs in a significant percentage of the human population and precludes eligibility for the treatment. 5 Acquired immunity after a single AAV-mediated gene therapy treatment occurs invariably in patients and precludes eligibility for a second treatment. In both forms of gene therapy, cDNA overexpression can only be used when dosage effects of the transgene product do not apply.…”

Section: Main Textmentioning

confidence: 99%

Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease

Ernst

Broeders

Herrero-Hernandez

et al. 2020

Molecular Therapy - Methods & Clinical Development

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We present an overview of clinical trials involving gene editing using clustered interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), or zinc finger nucleases (ZFNs) and discuss the underlying mechanisms. In cancer immunotherapy, gene editing is applied ex vivo in T cells, transgenic T cell receptor (tTCR)-T cells, or chimeric antigen receptor (CAR)-T cells to improve adoptive cell therapy for multiple cancer types. This involves knockouts of immune checkpoint regulators such as PD-1, components of the endogenous TCR and histocompatibility leukocyte antigen (HLA) complex to generate universal allogeneic CAR-T cells, and CD7 to prevent self-destruction in adoptive cell therapy. In cervix carcinoma caused by human papillomavirus (HPV), E6 and E7 genes are disrupted using topically applied gene editing machinery. In HIV infection, the CCR5 co-receptor is disrupted ex vivo to generate HIV-resistant T cells, CAR-T cells, or hematopoietic stem cells. In β-thalassemia and sickle cell disease, hematopoietic stem cells are engineered ex vivo to induce the production of fetal hemoglobin. AAV-mediated in vivo gene editing is applied to exploit the liver for systemic production of therapeutic proteins in hemophilia and mucopolysaccharidoses, and in the eye to restore splicing of the CEP920 gene in Leber’s congenital amaurosis. Close consideration of safety aspects and education of stakeholders will be essential for a successful implementation of gene editing technology in the clinic.

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“…5C and E). (3,4). In an effort to expand and improve the transduction efficiency and genetic engineering potential of AAV, our chimeric AAV variant design approach, combining VPs from several divergent serotypes, has generated an AAV, AAV-XV, with enhanced transduction characteristics for human T cells that address the requirement for high MOI.…”

Section: Generation Of New Chimeric Aav6 Capsid Variantsmentioning

confidence: 99%

AAV Capsid Chimeras with Enhanced Infectivity reveal a core element in the AAV Genome critical for both Cell Transduction and Capsid Assembly

Viney

Bürckstümmer²,

Mietzsch

et al. 2020

Preprint

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Adeno-associated viruses (AAV) have attracted significant attention in the field of gene and cell therapy due to highly effective delivery of therapeutic genes into human cells. The ability to generate recombinant AAV vectors compromised of unique or substituted protein sequences has led to the development of capsid variants with improved therapeutic properties. Seeking a novel AAV capable of enhanced transduction of human T cells for applications in immunotherapy, we have developed a unique capsid variant termed AAV XVivo (AAV-XV) that is a chimera of AAV12 VP1/2 sequences and the VP3 sequence of AAV6. This AAV chimera showed enhanced infection of human primary T cells and hematopoietic stem cells, and superiority over wildtype AAV6 for the genomic integration of DNA sequences either by AAV alone or in combination with CRISPR gene editing. AAV-XV demonstrated transduction efficiency equivalent to AAV6 at multiplicities of infection 2 logs lower, enabling T cell engineering at low AAV doses. Analyzing the protein coding sequence of AAV-XV revealed disruptions within the assembly-activating protein (AAP) which likely accounted for observed lower virus yield. A series of genome alterations reverting the AAP sequence back to wildtype had a negative impact on the enhanced transduction seen with AAV-VX, indicating overlapping functions within this sequence for both viral assembly and effective T cell transduction. Our findings show that AAV-XV is highly efficient at T cell engineering at low AAV dose and demonstrates the importance of AAP coding region in both viral particle assembly and cell infection.

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Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

Cited by 244 publications

References 125 publications

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease

AAV Capsid Chimeras with Enhanced Infectivity reveal a core element in the AAV Genome critical for both Cell Transduction and Capsid Assembly

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