Humoral immune responses to AAV gene therapy in the ocular compartment

Viral vectors can be utilised to deliver therapeutic genes to diseased cells. Adeno-associated virus (AAV) is a commonly used viral vector that is favoured for its ability to infect a wide range of tissues whilst displaying limited toxicity and immunogenicity. Most humans harbour anti-AAV neutralising antibodies (NAbs) due to subclinical infections by wild-type virus during infancy and these pre-existing NAbs can limit the efficiency of gene transfer depending on the target cell type, route of administration and choice of serotype. Vector administration can also result in de novo NAb synthesis that could limit the opportunity for repeated gene transfer to diseased sites. A number of strategies have been described in preclinical models that could circumvent NAb responses in humans, however, the successful translation of these innovations into the clinical arena has been limited. Here, we provide a comprehensive review of the humoral immune response to AAV gene therapy in the ocular compartment. We cover basic AAV biology and clinical application, the role of pre-existing and induced NAbs, and possible approaches to overcoming antibody responses. We conclude with a framework for a comprehensive strategy for circumventing humoral immune responses to AAV in the future.     

First description of a sex segregated aggregation of silky sharks (Carcharhinus falciformis) and the frequency and distribution of mating wounds off the tip of the Baja California Peninsula

Environmental Biology of Fishes - The silky shark (Carcharhinus falciformis) is a pelagic carcharhiniform shark species distributed globally in tropical and subtropical oceans. In this study, we...     

Possible implications for allosteric models of hemoglobin of the laws of combination with carbon monoxide under photodissociating conditions

It is shown that the data obtained by Brunori et al. on binding of carbon monoxide to hemoglobin in photodissociating conditions is explained by a simple allosteric model, the two-configuration exclusive-binding induced-fit model together with the simplest kinetic assumptions. Alternative models are considered. It is possible to calculate from the data of Brunori et al a dissociation rate constant for carbon monoxide which agrees well with an independently determined rate constant.     

Diffusion-related differences in elimination of inert gases from the lung

Partial pressures of intravenously infused acetylene, Freon 22, and isoflurane (gases with similar solubilities in blood but differing molecular weights) were compared in arterial and mixed venous blood and mixed expired gas of 13 anesthetized mongrel dogs to determine whether gas molecular weight influenced gas exchange. Analysis of covariance was used to account for the variables of ventilation-perfusion ratio, partition coefficient, and experimental run before individual gas effects were sought. A gas effect difference was observed such that the arterial fractional retention of isoflurane (mol wt 184.5) would be 12% higher than that of acetylene (mol wt 26) if the two gases had identical partition coefficients. This effect was neither significantly increased by positive end-expiratory pressure nor decreased by high-frequency oscillatory ventilation. To test whether the individual gas effect was greater with gases with disparate erythrocyte and plasma partition coefficients, the exchange of ethyl iodide (erythrocyte-to-plasma solubility ratio 8.1) and diethyl ether (solubility ratio 0.95) was compared in five dogs. A larger difference between the elimination of the two gases was observed than predicted from the differences in molecular weight. The observed individual gas effect appears to be diffusion related, influenced both by the molecular weight of a gas and its erythrocyte-plasma partition coefficient ratio.