Comparison of high-capacity and first-generation adenoviral vector gene delivery to murine muscle in utero

Bilbao, Roberto; Reay, Daniel P.; Wu, Eugene Y.; Zheng, Heng; Biermann, Volker; Kochanek, Stefan; Clemens, Paula R.

doi:10.1038/sj.gt.3302392

Cited by 25 publications

(22 citation statements)

References 26 publications

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“…In this approach, HDAds were found to be less toxic than the FGAd and able to drive stable transgene expression and restoration of the disarcoglycan complex. 52 Respiratory insufficiency due to progressive weakness of the diaphragm and other respiratory muscles is the main cause of death of DMD patients when they are in their late teens or early twenties. Therefore, diaphragmdirected gene therapy has been investigated in the mdx mouse using HDAd injected directly into the diaphragm exposed through a laparotomy.…”

Section: Hdad For Muscle Gene Therapymentioning

confidence: 99%

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

Brunetti‐Pierri

2008

Gene Ther

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Preclinical studies in small and large animal models using helper-dependent adenoviral vectors (HDAds) have generated promising results for the treatment of genetic diseases. However, clinical translation is complicated by the dosedependent, capsid-mediated acute toxic response following systemic vector injection. With the advancements in vectorology, a better understanding of vector-mediated toxicity, and improved delivery methods, HDAds may emerge as an important vector for gene therapy of genetic diseases and this report highlights recent progress and prospects in this field.

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Section: Hdad For Muscle Gene Therapymentioning

confidence: 99%

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

Brunetti‐Pierri

2008

Gene Ther

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“…When skeletal muscle fibers were transduced before birth (in utero at embryonic day 16), expression of the reporter protein was stable at least for 5 months despite the development of antibodies against the transgene and the adenoviral capsid. 106 However, in this case, the authors reported no loss of DNA copy number. Lower levels of toxicity compared to first-generation eneration Ad that resulted in higher survival rates of animals transduced in utero were also documented.…”

Section: Gutless Adenovirus and Immune Responsementioning

confidence: 52%

Gutless adenovirus: last-generation adenovirus for gene therapy

2005

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Last-generation adenovirus vectors, also called helper-dependent or gutless adenovirus, are very attractive for gene therapy because the associated in vivo immune response is highly reduced compared to first-and second-generation adenovirus vectors, while maintaining high transduction efficiency and tropism. Nowadays, gutless adenovirus is administered in different organs, such as the liver, muscle or the central nervous system achieving high-level and long-term transgene expression in rodents and primates. However, as devoid of all viral coding regions, gutless vectors require viral proteins supplied in trans by a helper virus. To remove contamination by a helper virus from the final preparation, different systems based on the excision of the helper-packaging signal have been generated. Among them, Cre-loxP system is mostly used, although contamination levels still are 0.1-1% too high to be used in clinical trials. Recently developed strategies to avoid/reduce helper contamination were reviewed. Gene Therapy (2005) 12, S18-S27.

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“…Furthermore, since the Ad vector does not integrate into the host genome, there is a potential for vector dilution by muscle growth between E-16 and 9 weeks of age as we have previously shown in the marker gene studies. 34 In mdx mice, the ongoing degeneration and regeneration of dystrophin-deficient muscle fibers results in an increasing percentage of fibers harboring centrally placed nuclei. In previous studies, treatment of postnatal pups prior to the first morphological evidence of muscle degeneration (approximately 2 weeks of age), resulted in a protective effect as indicated by a low level of centrally placed nuclei in dystrophin (+) fibers.…”

Section: Discussionmentioning

confidence: 99%

“…33 Previous in utero HC-Ad vector muscle transduction studies using a lacZ vector have shown that the human cytomegalovirus promoter provides high levels of b-gal expression in injected hindlimb muscles of C57BL/6 mice at 1 and 5 months after a single in utero muscle injection. 34 Also, for this current study, the vector titer became a limiting factor, since a maximum volume of 5 ml could be injected into the fetal hindlimb. Furthermore, since the Ad vector does not integrate into the host genome, there is a potential for vector dilution by muscle growth between E-16 and 9 weeks of age as we have previously shown in the marker gene studies.…”

Section: Discussionmentioning

confidence: 99%