Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity

Driesse, M.J.; Esandi, M.C.; Kros, JM; Avezaat, C. J. J.; Vecht, C. J.; Zürcher, C.; Velde, Ietje van der; Valerio, D.; Bout, A.; Smitt, Peter A. Sillevis

doi:10.1038/sj.gt.3301250

Cited by 67 publications

(28 citation statements)

References 35 publications

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“…[5][6][7] We, and others, have previously shown that injection of viral vectors into the cisterna magna, or trough lumbar puncture, might represent an efficient CNS delivery system in both small (mice) and large (non-human primates) animals. [8][9][10][11] Administration of vector into the cerebrospinal fluid (CSF) circulation, while bypassing the blood-brain barrier, allows viral vector transduction of neuroepithelial cells and delivery of transgene products to the whole CNS through the ventricular circulation. However, viral vector delivery via the CSF circulation still does not represent a realistic gene therapy option for chronic CNS disorders because of the short-term expression and residual immunogenicity of the vectors so far tested (for example, first-generation herpes simplex virus type 1-derived vectors or first generation Ad vectors).…”

Section: Introductionmentioning

confidence: 99%

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

et al. 2008

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Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity.Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4 + CD69 À CD25 + Foxp3 + ) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.

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Section: Introductionmentioning

confidence: 99%

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

et al. 2008

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“…1,2 In vivo administration of Ad vectors is usually associated with dose-dependent toxicity that has been linked to activation of both innate and adaptive immune responses. [3][4][5][6][7][8][9][10][11][12] Systemically administered Ad vector is efficiently distributed to different tissues, [13][14][15][16] exerting its effects both locally and systemically.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naïve and pre-immunized mice

et al. 2005

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Toxicity associated with in vivo administration of adenovirus (Ad) vectors has been linked to activation of both innate and adaptive immune responses. Pre-existing immunity to the prevalent Ad serotypes, acquired by the majority of the human population as a result of natural infections, has the potential to modulate vector efficacy and safety. Previously, we evaluated some aspects of toxicity from systemic Ad vector in vector-naïve and pre-immunized rhesus monkeys. In this report, we summarize data from several studies analyzing toxic effects from systemically administered E1/E3-deleted Ad vector in vector-naïve and pre-immunized C57BL/6 mice. Our results indicate that pre-immunization can be associated with increased mortality shortly after systemic administration of Ad. Transient leukopenia and thrombocytopenia were observed early post vector infusion in both vector-naïve and pre-immunized animals. Preexposure to the vector did not prevent induction of proinflammatory cytokines; however, pre-immunized mice showed less tissue toxicity. Growth of bone marrow myeloid and erythroid progenitors was transiently inhibited in preimmunized animals, but only the myeloid progenitors were affected in vector-naïve animals. In summary, pre-existing immunity to Ad vector substantially modifies host immune responses to systemic Ad vector.

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“…46 Vectors can drain from the brain to the neck lymph nodes at least in non-human primates. 47,48 In rodents, drainage to lymph nodes seems to occur after administration into the ventricles, but not following intraparenchymal injection. 45 Given the fact discussed above that rAAV does not induce cellular immunity in laboratory models, even if administered systemically, it is not surprising that it does not elicit cellular immunity, when administered into the CNS of animals either.…”

Section: Immunity In the Cnsmentioning

confidence: 99%

AAV for pain: steps towards clinical translation

Beutler

Reinhardt

2009

Gene Ther

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Recombinant adeno-associated virus (rAAV) vectors consisting of self-complementary genomes and packaged in certain capsids can target primary sensory neurons efficiently and can control neuropathic pain long term by expressing opioid or non-opioid analgesic genes. This review examines the therapeutic potential of the approach in five sections: Pain control in oncology (including a discussion of cancer centers as translational pain research environment); vector biology; safety considerations and immunological lessons learned from rAAV clinical trials of other disorders; development of intrathecal rAAV therapy in rodent models of pain; and preclinical steps towards clinical translation of rAAV for pain. In the field of analgesic drug development, clinical validation of new approaches identified in rodents is currently a critical limiting step. Small-molecule therapeutics suitable as conventional drugs to probe novel targets in clinical trials are often unavailable. In this context, gene therapy could fill an important gap in the drug development process facilitating first-into-human trials of untested targeted treatments, each instantiated as a therapeutic gene.

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Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity

Cited by 67 publications

References 35 publications

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naïve and pre-immunized mice

AAV for pain: steps towards clinical translation

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