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Twenty years ago, a mold contaminating a petri dish in the laboratory of Judah Folkman, MD, yielded one of the most potent, broadly acting angiogenesis inhibitors known. Called TNP-470, it suppressed a wide range of cancers in Phase I and II clinical trials by halting blood-vessel growth. Sadly, trials stopped after neurologic side effects surfaced in some patients. Now, however, Ofra Benny, PhD, in the Children's Hospital Boston Vascular Biology Program, has created "pom-pom"-shaped nanoparticles, with TNP-470 at the core, that appear to be nontoxic, can be taken orally, and retain all of TNP-470's activity, inhibiting a variety of tumors in mice and even preventing liver metastases. If results hold up in humans, Benny's formulation (called Lodamin) could be a useful preventive or maintenance therapy for many cancers. (Nature Biotechnology, June 29, 2008)
Up to 35 percent of babies surviving prematurity are left with neurologic impairment. Now, research from the Children's lab of Frances Jensen, MD, suggests that memantine (Namenda), originally developed for Alzheimer's disease, may help break the cycle of brain damage. Existing neurologic drugs don't work in newborns, but over the past decade, Jensen and colleagues have been finding cellular targets unique to these babies' immature brains—as well as drugs that can hit them. Memantine, for example, blocks NMDA receptors, which premature newborns have in abundance and that make them especially vulnerable to brain injury. If the drug proves to be safe in premature newborns, Jensen hopes to conduct a clinical trial of its efficacy. (Journal of Neuroscience, June 25, 2008)
One of the biggest challenges in tissue engineering has been getting the implanted tissues and organs the blood supply needed to keep them alive. Now, Juan Melero-Martin, PhD, Joyce Bischoff, PhD, and colleagues in Children's Vascular Biology Program have successfully grown functioning human blood vessels in mice, using progenitor cells from blood or bone marrow. The cells formed dense networks of two-layered blood vessels within seven days, as shown below, without the need for genetic manipulation to improve their growth. If the growth can be sped up further, this practical advance could also provide a new way to treat heart attacks and other conditions where tissues are starved for blood. (Circulation Research, July 2008)
Probing the heart's earliest origins, William Pu, MD, and research fellow Bin Zhou, MD, both of Children's Department of Cardiology, have pinpointed a previously unrecognized group of cardiac progenitor cells, advancing the hope of being able to regenerate injured heart tissue. These stem cells, located on the surface of the hearts of developing mice, produce not only cardiomyocytes (heart muscle cells), but also smooth muscle cells, endothelial cells and fibroblasts—all the cell types that would be needed to regenerate the heart's tissues. If these progenitor cells could be coaxed to grow in an adult heart, and turned toward making the right kinds and numbers of cells, they could offer a new approach to treating heart failure. (Nature, July 3, 2008)
The conventional view of stem-cell differentiation assumes that cells are instructed to progress along prescribed signaling pathways. However, new evidence supports a "systems" view—the idea that differentiation is the collective "decision" of multiple genes. The genes form a network that ultimately leads to just a few endpoints—just as a marble can take many paths down a hill, only to arrive in the same handful of valleys. Working with populations of seemingly identical blood stem cells, researchers from Children's Vascular Biology Program showed that cells slowly move in and out of a "primed" state, allowing them to become red or white blood cells when conditions are right. By harnessing this built-in variability, scientists might be able to differentiate stem cells more efficiently, the researchers say. (Nature, May 22, 2008)
A rare iron deficiency disorder that doesn't respond to iron supplements is providing new insight into iron deficiency generally. Children's pathologist Mark Fleming, MD, D. Phil, and pediatric hematologist Nancy Andrews, MD, PhD (formerly of Children's), studied five extended families with the rare disorder, and found a variety of mutations in a gene called TMPRSS6. The mutations cause over-production of hepcidin, a hormone that reduces the body's ability to absorb and use iron. Although this syndrome is quite rare, the findings suggest that stimulating the TMPRSS6 protein may benefit other patients with anemia. Conversely, blocking TMPRSS6 to encourage hepcidin production may help patients with iron overload disorders. (Nature Genetics, April 13, 2008)
Although sickle-cell disease is a single-gene disorder, symptoms can range from mild to devastating. Now, researchers at Children's, Dana-Farber Cancer Institute and the Broad Institute report five gene variants that predict disease severity by influencing blood levels of fetal hemoglobin, a form of hemoglobin that's gradually replaced by adult hemoglobin after birth. Past research at Children's helped establish that the more fetal hemoglobin that is retained, the more benign sickle-cell symptoms will be. The clinical usefulness of these gene variants must be validated, but understanding why fetal hemoglobin levels vary could eventually allow doctors to ameliorate sickle-cell pain crises and other severe symptoms. (PNAS, July 14, 2008)
Chemotherapy drugs often don't reach their targets due to leaky, twisted blood vessels feeding the tumors. Kaustabh Ghosh, PhD, working in the lab of Donald Ingber, MD, PhD, interim co-director of Children's Vascular Biology Program, has found an explanation: elevated tension and contractility in the cells lining tumor capillaries. Unlike normal capillary cells, these cells respond abnormally to mechanical cues, such as stretching of the blood vessel wall as fluid pulses through, leading to irregularly shaped capillaries and gaps between cells that cause vessel leakiness. A protein called Rho-associated kinase is the likely culprit; inhibiting its function dissipated cell tension and normalized mechanical responsiveness and blood vessel architecture. Ghosh and Ingber envision combining this approach with chemotherapy to further improve cancer treatment. (PNAS, Aug. 6, 2008)
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