News From The Journal Of Clinical Investigation, July 1, 2009

Main Category: Genetics
Also Included In: Urology / Nephrology;  Biology / Biochemistry;  Cardiovascular / Cardiology
Article Date: 03 Jul 2009 - 1:00 PDT

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GENE THERAPY: Defining immune pathways limiting gene therapy

In gene therapy, recombinant adeno-associated viruses (AAVs) are commonly used vehicles for delivering the therapeutic gene into target cells. One factor limiting the clinical application of such vehicles is that the immune system often mounts a response against the AAV vehicle. Understanding how AAVs activate the immune system is therefore of central importance for developing approaches to eliminate this hurdle to clinical use. Yiping Yang and colleagues, at Duke University Medical Center, Durham, have now identified a pathway by which AAVs activate the immune system in mice. Specifically, AAVs were found to activate mouse immune cells known as pDCs via the protein TLR9. This, in turn, activated a signaling pathway that caused pDCs to produce immune molecules known as type I IFNs. In mice, this signaling pathway led to activation of AAV-targeted immune cells (in particular CD8+ T cells) and loss of expression of the gene being carried by the AAVs. As in vitro evidence that AAVs activate this signaling pathway in human pDCs was also obtained, the authors suggest that interfering with this pathway may improve the clinical outcome of gene therapy using AAV vehicles.

TITLE: The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice

NEPHROLOGY: Damaged kidneys want the protein CSF-1 to stimulate repair

Remarkably, the kidney is able to fully heal following exposure to acute damage caused by numerous things. As most forms of acute kidney damage are accompanied by restriction of the blood supply to the kidney (ischemia), mouse models of ischemia/reperfusion (i.e., blood supply restriction followed by restoration of the normal blood supply) are commonly used to study the process of kidney repair. Using this approach, Vicki Kelley and colleagues, at Brigham and Women's Hospital, Boston, have determined that the molecule CSF-1 has an important role in kidney repair following ischemia/reperfusion.

In the study, mice injected with CSF-1 showed more rapid kidney healing following ischemia/reperfusion. Conversely, blocking the protein to which CSF-1 binds (CSF-1R) worsened kidney damage. Further analysis indicated that CSF-1 promoted mouse kidney repair both indirectly, via immune cells known as macrophages, and directly, by signaling to kidney cells known as tubular epithelial cells. Specifically, CSF-1 induced the tubular epithelial cells to proliferate and reduced the number of cells dying by a process known as apoptosis. As CSF-1 had similar in vitro effects on human tubular epithelial cells, the authors suggest that modulating the CSF-1/CSF-1R pathway might be beneficial in the context of acute kidney damage.

TITLE: CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice

DEVELOPMENT: Developing blood vessels leaving the heart need the protein FAK

Researchers at the University of California, San Francisco, have provided new insight into the molecular pathways that control the development of the blood vessels that transport blood out of the mouse heart. The clinical relevance of this is highlighted by the fact that a deficiency in this molecular pathway led to cleft palate and heart defects resembling those observed in individuals with DiGeorge syndrome, a rare congenital disease.

Neural crest cells are crucial for the correct development of the heart, in particular the blood vessels that transport blood out of the heart. To investigate the molecular pathways controlling this, the researchers, led by Ainara Vallejo-Illarramendi and Louis Reichardt, generated mice lacking the protein FAK in neural crest cells. These mice exhibited the cleft palate and heart defects seen in individuals with DiGeorge syndrome. Detailed analysis indicated that the role of FAK in the normal development of the blood vessels that transport blood out of the mouse heart is to promote the activation of signaling proteins such as Crkl and Erk1/2. Thus, FAK is essential for normal mouse development.

TITLE: Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development

Source:
Karen Honey
Journal of Clinical Investigation