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Adenovirus type 5 (Ad5) specifically binds coagulation factor X (FX), and FX is normally essential for intravenously injected Ad5 vectors to transduce the liver. We demonstrate that the ability of FX to enhance liver transduction by Ad5 vectors is due to an unexpected ability of FX to protect Ad5 from attack by the classical complement pathway. In vitro, naive mouse serum neutralized Ad5 when FX was blocked from binding Ad5. This neutralization was mediated by natural IgM and the classical complement pathway. In vivo, FX was essential for Ad5 vectors to transduce the livers of wild-type mice, but FX was not required for liver transduction in mice that lack antibodies, C1q or C4. We conclude that Ad5 recruits FX as a defense against complement and that the sensitivity of Ad5 to inactivation by complement must be taken into account when designing vectors for systemic gene therapy., When gene therapy vectors are injected systemically, they immediately come into contact with plasma proteins that can profoundly alter vector tropism and biodistribution. Like many viruses, Ad5 can inter-act with [...]

Non-replicating adenovirus vectors are being developed as vehicles for gene transfer into cells of the nervous system. An important requirement for successful gene transfer is the absence of deleterious cytotoxic or inflammatory side effects of the delivery system. Despite offering relatively stable reporter gene expression, currently available adenovirus vectors also elicit immune responses in the brain, both at the site of vector delivery and at synaptically linked distant sites. However, although an anti-viral T-lymphocyte response eliminates the vector and damages local tissue in many peripheral organs, the immune response to adenovirus in the brain is less effective and enables the vector to persist. Nevertheless, in this persistent state the adenovirus vector remains a potential target for a destructive immune response that can also cause local demyelination. The development of strategies to minimize this damaging immune response, through either vector modification or immunomodulation, will be crucial for the future success of genetic therapies in the brain.

This article explores the nature and extent of barriers to access to justice that older persons experience, including those with mental health conditions. It finds that access to justice-the right to fair, prompt and responsive decisions by administrative decision-makers and equal access to courts and tribunals to obtain timely and effective remedies-is not only an important right in itself but also enables the enjoyment of many other human rights. Yet older persons, particularly those with mental health conditions, face a significant "justice gap." Ageist attitudes, laws and practices interact with other forms of bias such as mentalism, sexism, ableism, racism, homophobia, and heterosexism exacerbating older persons' disadvantage and marginalization, particularly those with mental health conditions, and older indigenous persons. These discriminatory practices, together with the phenomena of elder abuse, all severely limit older persons' access to timely and responsive justice. International and national standards, both general and specific to older persons, have been shown to be inadequate to respond to this justice gap. An international standard in the form of a binding legal obligation that specifically addresses older persons' rights of access to justice is needed urgently as part of a new international treaty on the human rights of older persons. [ABSTRACT FROM AUTHOR]

Natural IgM inhibits gene transfer by adenovirus type 5 (Ad5) vectors. We show that polyreactive natural IgM antibodies bind to Ad5 and that inhibition of liver transduction by IgM depends on Kupffer cells. By manipulating IgM concentration in vivo, we demonstrate that IgM inhibits liver transduction in a concentration-dependent manner. We further show that differences in natural IgM between BALB/c and C57BL/6 mice contribute to lower efficiency of Ad5 gene transfer in BALB/c mice. [ABSTRACT FROM AUTHOR]

Innate immune responses are a major barrier to safe systemic gene therapy with adenovirus (Ad) vectors. We show that intravenous (IV) injection of rats with Ad5 vectors causes a novel rapid shock reaction that involves hypotension, hemoconcentration, tissue edema, and vasocongestion, with notable pathology in the pancreas and the gastrointestinal system. We show for the first time that this reaction is dependent on platelet-activating factor (PAF), a lipid signaling molecule that is a known shock inducer. Ad upregulated PAF within 5 minutes in vivo, and antagonists of the PAF receptor were able to prevent Ad-induced shock. Ad upregulated PAF via the reticuloendothelial system (RES), because splenectomy or depletion of phagocytes blocked the ability of Ad to induce both PAF and shock. Rats were considerably more sensitive to Ad-induced shock than were mice, but PAF mediated shock in both species. Other Ad-induced innate immune responses such as cytokine induction and thrombocytopenia were not mediated by PAF. In summary, systemic IV injection of Ad stimulates the RES to upregulate PAF within a matter of minutes, which results in shock. The identification of this novel pathway suggests strategies to improve the safety of systemic gene therapy with Ad vectors. [ABSTRACT FROM AUTHOR]

Kupffer cells (KCs) rapidly remove intravenously injected adenovirus (Ad) vectors from the circulation. A better understanding of the mechanisms involved could suggest strategies to improve Ad gene delivery by suppressing or evading KC uptake. We recently showed that clearance of Ad type 5 vectors by KCs does not involve the interaction of Ad with the well-established Ad receptors, namely, integrins or the coxsackievirus and Ad receptor (J. S. Smith, Z. Xu, J. Tian, S. C. Stevenson, and A. P. Byrnes, Hum. Gene Ther. 19:547-554, 2008). In the current study, we systematically quantified the contributions of various receptors and plasma proteins to the clearance of Ad by KCs. We found that scavenger receptors are a predominant mechanism for the clearance of Ad by KCs. In addition, we found that Ad is opsonized by natural immunoglobulin M antibodies and complement and that these opsonins play a contributory role in the clearance of Ad by KCs. We also examined additional mechanisms that have been postulated to be involved in the clearance of Ad, including the binding of Ad to platelets and vitamin K-dependent coagulation factors, but we found that neither of these were required for the clearance of Ad by KCs. [ABSTRACT FROM AUTHOR]