Modulation of immune responses in lentiviral vector-mediated gene transfer

Annoni, Andrea; Gregori, Silvia; Naldini, Luigi; Cantore, Alessio

doi:10.1016/j.cellimm.2018.04.012

Cited by 58 publications

(42 citation statements)

References 120 publications

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“…For gene delivery, essential viral coding regions (e.g., gag , pol , and env ) are removed from the LV genome, and instead provided by separate expression plasmids for in vitro packaging (Milone and O’Doherty, 2018 ). This removal of viral genes ensures that the immunogenicity of LV is relatively low, although not absent (Annoni 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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“…Lentiviral vectors, on the other hand, are able to integrate within the host genome, have an expression cassette with doubled capacity compared to AAV, and present lower pre-existing immunity to LV elements (109,110). These features allow the design of LV that can contain combinations of transcriptional and post-transcriptional regulation sequences, i.e., cell typespecific promoters and microRNA target sequences, in addition to the therapeutic transgene.…”

Section: Discussionmentioning

confidence: 99%

Escape or Fight: Inhibitors in Hemophilia A

Merlin

Follenzi

2020

Front. Immunol.

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Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.

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“…Rabies virus with double deletion of G/L has reduced the cytotoxicity and gene expression [35]. Lentiviruses packaged by modi ed RVG have high retrograde transport e ciency [25] but may induce host immune responses [36,37] or lead to tumorigenesis by random insertion into the host genome [38]. CAV-2 has relatively low immunogenicity, large cloning capacity [39,40], and enhanced retrograde labelling e ciency after compensation of the CAV-2 receptor in input neurons [6] but only moderate levels of gene expression [41] and di culties in preparation [42].…”

Section: Introductionmentioning

confidence: 99%

AAV9-Retro mediates efficient transduction with axon terminal absorption and blood–brain barrier transportation

Lin

Zhong

et al. 2020

Preprint

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Recombinant adeno-associated viruses (rAAVs), particularly those that permit efficient gene transfer to neurons from axonal terminals or across the blood–brain barrier, are useful vehicles for structural and functional studies of the neural circuit and for the treatment of many gene-deficient brain diseases that need to compensate for the correct genes in every cell in the whole brain. However, AAVs with these two advantages have not been reported. Here, we describe a new capsid engineering method, which exploits the combination of different capsids and aims to yield a capsid that can provide more alternative routes of administration that are more suitable for the wide-scale transduction of the central nervous system (CNS). A new AAV variant, AAV9-Retro, was developed by inserting the 10-mer peptide fragment from AAV2-Retro into the capsid of AAV9, and the biodistribution properties were evaluated in mice. By intracranial and intravenous injection in the mice, we found that AAV9-Retro can retrogradely infect projection neurons with an efficiency comparable to that of AAV2-Retro and retains the characteristic of AAV9, which can be transported across the nervous system. Our strategy provides a new tool for the manipulation of neural circuits and future preclinical and clinical treatment of some neurological and neurodegenerative disorders.

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Modulation of immune responses in lentiviral vector-mediated gene transfer

Cited by 58 publications

References 120 publications

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Escape or Fight: Inhibitors in Hemophilia A

AAV9-Retro mediates efficient transduction with axon terminal absorption and blood–brain barrier transportation

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