X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.

Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction.

Conduction block in micropatterned cardiomyocyte cultures replicating the structure of ventricular cross-sections.

Aims: Structural and functional heterogeneities in cardiac tissue have been implicated in conduction block and arrhythmogenesis. However, the propensity of specific sites within the heart to initiate conduction block has not been systematically explored. We utilized cardiomyocyte cultures replicating the realistic, magnetic resonance imaging-measured tissue boundaries and fibre directions of ventricular cross-sections to investigate their roles in the development of conduction block.

Tumor microvascular permeability is a key determinant for antivascular effects of doxorubicin encapsulated in a temperature sensitive liposome.

Previous data have demonstrated that doxorubicin (DOX) released from a lysolecithin-containing thermosensitive liposome (LTSL) can shut down blood flow in a human tumor xenograft (FaDu) in mice when the treatment is combined with hyperthermia (HT), suggesting that LTSL-DOX is a potential antivascular agent. To further understand mechanisms of the treatment, we investigated effects of LTSL-DOX (5 mg/kg body weight) plus HT (42 degrees C, 1 h) on microcirculation in another tumor (a murine mammary carcinoma, 4T07) implanted in mouse dorsal skin-fold chambers and dose responses of tumor (FaDu and 4T07) and endothelial cells to LTSL-DOX or free DOX with or without HT. We observed that LTSL-DOXHT could significantly reduce blood flow and microvascular density in 4T07 tumors.

Systemic dissemination of viral vectors during intratumoral injection.

Intratumoral injection is a routine method for local viral gene delivery that may improve interstitial transport of viral vectors in tumor tissues and reduce systemic toxicity. However, the concentration of transgene products in normal organs, such as in the liver, may still exceed normal tissue tolerance if the products are highly toxic. The elevated concentration in normal tissues is likely to be caused by the dissemination of viral vectors from the tumor.