Wild-type AAV Insertions in Hepatocellular Carcinoma Do Not Inform Debate Over Genotoxicity Risk of Vectorized AAV

Nault, Jean–Charles; Mami, I.; Bella, Tiziana La; Datta, Shalini; Imbeaud, Sandrine; Franconi, Andrea; Mallet, Maxime; Couchy, Gabrielle; Letouzé, Éric; Pilati, Camilla; Verret, Benjamin; Blanc, Jean‐Frédéric; Balabaud, Charles; Caldéraro, Julien; Laurent, Alexis; Letexier, Mélanie; Bioulac‐Sage, Paulette; Calvo, Fabien; Zucman‐Rossi, Jessica

doi:10.1038/mt.2016.47

Cited by 34 publications

(27 citation statements)

References 8 publications

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“… 165 The analyses showed insertions of AAV sequences, mostly representing fragments of the ITR, in HCC pro-oncogenes, which in turn were possibly positively selected due to the ITR transactivation effect. 166 These observations were recently corroborated by the identification of liver-specific enhancer-promoter elements in the wild-type AAV2 genome. These elements (present in a stretch of 124 nt) were found to be close to the right-hand ITR and within the 163-nt common insertion region of the AAV genome, which was previously identified in HCC biopsies.…”

Section: Main Textmentioning

confidence: 81%

Emerging Issues in AAV-Mediated In Vivo Gene Therapy

Colella

Ronzitti

Mingozzi

2018

Molecular Therapy - Methods & Clinical Development

644

531

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In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others. Clinical translation of novel and effective “therapeutic products” is, however, a long process that involves several cycles of iterations from bench to bedside that are required to address issues encountered during drug development. For the AAV vector gene transfer technology, several hurdles have emerged in both preclinical studies and clinical trials; addressing these issues will allow in the future to expand the scope of AAV gene transfer as a therapeutic modality for a variety of human diseases. In this review, we will give an overview on the biology of AAV vector, discuss the design of AAV-based gene therapy strategies for in vivo applications, and present key achievements and emerging issues in the field. We will use the liver as a model target tissue for gene transfer based on the large amount of data available from preclinical and clinical studies.

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Section: Main Textmentioning

confidence: 81%

Emerging Issues in AAV-Mediated In Vivo Gene Therapy

Colella

Ronzitti

Mingozzi

2018

Molecular Therapy - Methods & Clinical Development

644

531

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“…These combined features have led to AAV becoming the premier clinical gene therapy vector and its recent regulatory approval for the treatment of several conditions (High and Roncarolo, 2019 ). However, AAV gene therapy is not entirely infallible, as wild type AAV infections have been linked with human disease (Nault et al, 2016 ); however, potential solutions to overcome these and other concerns to drive human AAV gene therapy are continuing (Colella et al, 2018 ). Nonetheless, many more clinical trials of AAV-mediated gene therapy are ongoing or planned, including several involving intramuscular administration (although not necessarily for neuronal transduction).…”

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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“…Therefore, the hepatocellular carcinoma was likely caused by the metabolic complications of OTC deficiency rather than the adenoviral vector [13]. The ongoing clinical trial uses an adeno-associated virus vector that can insert its DNA into human genome, but it is still not established whether adeno-associated virus genome insertion is tumorigenic [14, 15]. HCA in OTC-deficient patients has not been previously reported.…”

Section: Discussionmentioning

confidence: 99%