Article

A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency

Institute for Human Gene Therapy and Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
Human Gene Therapy (Impact Factor: 3.62). 02/2002; 13(1):163-75. DOI: 10.1089/10430340152712719
Source: PubMed

ABSTRACT Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize metabolism. An E1- and E4-deleted vector based on adenovirus type 5 and containing human OTC cDNA was infused into the right hepatic artery in adults with partial OTCD. Six cohorts of three or four subjects received 1/2 log-increasing doses of vector from 2 x 10(9) to 6 x 10(11) particles/kg. This paper describes the experience in all but the last subject, who experienced lethal complications. Adverse effects included a flu-like episode and a transient rise in temperature, hepatic transaminases, thrombocytopenia, and hypophosphatemia. Humoral responses to the vector were seen in all research subjects and a proliferative cellular response to the vector developed in apparently naive subjects. In situ hybridization studies showed transgene expression in hepatocytes of 7 of 17 subjects. Three of 11 subjects with symptoms related to OTCD showed modest increases in urea cycle metabolic activity that were not statistically significant. The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur.

0 Followers
 · 
108 Views
  • Source
    • "Hepatocytes have proved highly susceptible to transduction by a number of viral vectors (Fig. 2). Advanced studies have shown that both adenovirus and AAV vectors can be used to transduce the liver with high efficiency in vivo in animal studies (Jaffe et al., 1992; Li et al., 1993; Nathwani et al., 2006) and in clinical trials (Raper et al., 2002; Nathwani et al., 2011). No significant side effects have been reported in clinical trials for AAV. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment for most persistent viral infections consists of palliative drug options rather than curative approaches. This is often because long-lasting viral DNA in infected cells is not affected by current antivirals, providing a source for viral persistence and reactivation. Targeting latent viral DNA itself could therefore provide a basis for novel curative strategies. DNA cleavage enzymes can be used to induce targeted mutagenesis of specific genes, including those of exogenous viruses. Although initial in vitro and even in vivo studies have been carried out using DNA cleavage enzymes targeting various viruses, many questions still remain concerning the feasibility of these strategies as they transition into preclinical research. Here, we review the most recent findings on DNA cleavage enzymes for human viral infections, consider the most relevant animal models for several human viral infections, and address issues regarding safety and enzyme delivery. Results from well-designed in vivo studies will ideally provide answers to the most urgent remaining questions, and allow continued progress toward clinical application.
    Virology 01/2014; 454-455(1). DOI:10.1016/j.virol.2013.12.037 · 3.28 Impact Factor
  • Source
    • "When the therapeutic effect can be achieved upon expression of a single gene in post‐mitotic tissue, non‐integrating vector systems are favoured. Indeed, in one of the first in vivo clinical trials, an attenuated adenovirus‐derived vector was used for the treatment of ornithine transcarbamylase deficiency (OTCD), an inborn disease of urea synthesis (Raper et al, 2002). Vector‐ and transgene‐elicited immunoreactions were initially of concern in the in vivo application of vector particles, as documented by the death of one out of the 17 subjects treated in the OTCD trial, which was caused by a massive immune reaction against the capsid of the infused adenoviral vector (Raper et al, 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders.
    EMBO Molecular Medicine 11/2013; 5(11). DOI:10.1002/emmm.201202287 · 8.25 Impact Factor
  • Source
    • "Thus, we conclude that liver toxicity is not occurring when adenovectors are delivered intramuscularly at doses up to 2 × 10 11 PU/VP and that the elevated cholesterol and triglycerides are simply a reflection of an inflammatory response to vaccination. Importantly, despite reports of liver toxicity when similar or higher doses of adenovectors have been delivered by routes other than the intramuscular route studied here (Harvey et al., 2002; Raper et al., 2002), we have not noted any particular or consistent impact of vaccination on the liver – either in liver function tests, such as ALT, AST, or alkaline phosphatase, or by gross or histopathology (as discussed above). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Vaccine Research Center has developed vaccine candidates for different diseases/infectious agents (including HIV-1, Ebola, and Marburg viruses) built on an adenovirus vector platform, based on adenovirus type 5 or 35. To support clinical development of each vaccine candidate, pre-clinical studies were performed in rabbits to determine where in the body they biodistribute and how rapidly they clear, and to screen for potential toxicities (intrinsic and immunotoxicities). The vaccines biodistribute only to spleen, liver (Ad5 only), and/or iliac lymph node (Ad35 only) and otherwise remain in the site of injection muscle and overlying subcutis. Though approximately 10(11) viral particles were inoculated, already by Day 9, all but 10(3) to 10(5) genome copies per mu g of DNA had cleared from the injection site muscle. By three months, the adenovector was cleared with, at most, a few animals retaining a small number of copies in the injection site, spleen (Ad5), or iliac lymph node (Ad35). This pattern of limited biodistribution and extensive clearance is consistent regardless of differences in adenovector type (Ad5 or 35), manufacturer's construct and production methods, or gene-insert. Repeated dose toxicology studies identified treatment-related toxicities confined primarily to the sites of injection, in certain clinical pathology parameters, and in body temperatures (Ad5 vectors) and food consumption immediately post-inoculation. Systemic reactogenicity and reactogenicity at the sites of injection demonstrated reversibility. These data demonstrate the safety and suitability for investigational human use of Ad5 or Ad35 adenovector-based vaccine candidates at doses of up to 2 x 10(11) given intramuscularly to prevent various infectious diseases.
    Journal of Immunotoxicology 08/2008; 5(3):315-35. DOI:10.1080/15376510802312464 · 1.91 Impact Factor
Show more