F.H. Sheikh

Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice

Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.

Palliative care in cardiac transplantation: an evolving model

It is currently estimated that 5.7 million Americans live with heart failure. Of these, less than 3000 will receive a heart transplant this year, according to the US Department of Health and Human Services Organ Procurement and Transplantation Network. With successful transplantation can come significant emotional and physical symptoms that are not always addressed. Although palliative care is an interdisciplinary subspecialty designed to alleviate multiple domains of suffering in serious illness, many mistakenly associate it solely with the end of life. Traditionally associated with cancer, research into the role of palliative care in other chronic illnesses and complex life-changing therapies such as solid organ transplantation remains scarce but is nonetheless developing. Here, we try to investigate a potential role for palliative care for heart transplant recipients. Early research thus far has demonstrated importance of early involvement of palliative care teams and the significant improvement of physical and emotional symptoms in the pre- and post-transplant period. Nevertheless, more research is warranted to determine the ideal timing of palliative care integration, the effects on health care resource utilization, and whether improving quality of life can affect morbidity and mortality. By understanding these critical elements and others we may be able to develop a model for the role of palliative care for heart transplant patients.