Raper, SE, Yudkoff, M, Chirmule, N, Gao, GP, Nunes, F, Haskal, ZJ et al.. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 13: 163-175
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.
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- "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. "
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
- "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). "
Article: Gene therapy on the move[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
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- "These pathways rely on pattern recognition receptors that recognize a variety of epitopes on pathogenic microorganisms, and lead to cytokine secretion and enhanced stimulation of adaptive immunological responses as well as promotion of direct cytotoxic effects. Early efforts to utilize adenovirus to deliver genes to the liver showed that such innate immune stimulation was critical for an enhanced cytotoxic response to adenovirus vectors, and was instrumental in the tragic death of Jesse Gelsinger, who died of a systemic inflammatory response just 4 days after receiving 6 × 1011 viral particles/kg of an FG-Ad designed to treat his ornithine transcarbamylase deficiency.20 Another patient treated previously at the same dose with the same vector had only mild, transient side effects,21 indicating that patient-to-patient variations in the intensity of innate immune responses are significant and perhaps affected by pre-existing adaptive immunity. Subsequent animal studies, however, have failed to replicate the particularly lethal combination of symptoms observed in the ornithine transcarbamylase trial, even with pre-immunization, and so the precise cause of Mr Gelsinger’s death remains a mystery.22 "
ABSTRACT: Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX) and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should lead to vector designs that result in higher FIX activity at lower vector doses and with reduced host immune responses to the vector and the transgene product.The Application of Clinical Genetics 10/2013; 6:91-101. DOI:10.2147/TACG.S31928