New Genetic And Stem-Cell Technology To Grow Sheets Of Skin

Somewhere in Germany’s Ruhr valley, a nine-year-old boy is doing what children do: playing football, joking around with friends and going to school. Two years ago, he was confined to a hospital bed, dying of a rare and cruel genetic skin disease. The boy had junctional epidermolysis bullosa, or JEB. He, like other people with the disease, carried a mutation in a gene that controls the integrity of the skin. Doctors could only try to ease his suffering as some 80% of his skin simply fell away.

A team of Italian researchers came to his aid by combining stem-cell techniques with gene therapy. As a young scientist at Harvard Medical School in Boston, Massachusetts, in the 1980s, Michele De Luca — the lead author of the new study — watched pioneers in skin regeneration learn to grow small sheets of skin from cells taken from burns patients, and to use them in grafts. He extended the work in Italy, applying new genetic and stem-cell technologies. He developed ways to generate stem cells from human skin, replace disease-causing genes in them and grow sheets of healthy skin on scaffolds in the lab.

He chose JEB for his first clinical trial, which he registered with the Italian Medicines Agency in 2002. Four years later, he reported his first success, in which he created healthy skin patches from biopsies to replace small areas of sloughed-off skin on the legs of a patient with a form of JEB (F. Mavilio et al. Nature Med. 12, 1397–1402; 2006). New European Commission regulations introduced in 2007 required him to pause the project while he created facilities adhering to ‘good manufacturing practices’ (GMPs) and a spin-off company to meet the demands for strengthened oversight of cell-based therapies.

Having a company refocused his team’s attention on a different type of stem-cell therapy, one likely to yield a product for the market faster. Holoclar, a treatment that replaces the eye’s cornea in a form of blindness, became the world’s first commercial stem-cell therapy in 2015.

A few months later, at the University of Modena, De Luca got a call out of the blue from doctors in Germany who were trying to treat the little boy. Because the therapy had been in a clinical trial, albeit one on hold at the time, and because De Luca could provide GMP services, German regulatory authorities quickly approved the one-off compassionate use of the JEB therapy. Surgeons in Germany sent a skin biopsy to Modena, and two major skin transplants followed. Six months after the initial biopsy, the boy returned to school. During the many months since, he has not had so much as a blister, and loves to show off his ‘new skin’. By their nature, highly personalized treatments using gene therapies and products derived from an individual’s stem cells are likely to be applicable to only a subset of patients.

Scientists and clinicians have presented the details of the recovery in Nature (T. Hirsch et al.Nature http://dx.doi.org/10.1038/nature24487; 2017). This major clinical development was based on decades of basic research. The clinical data gathered during 21 months of follow-up after the boy’s treatment have also led to major insights into human skin biology, as discussed in an accompanying News & Views (M. Aragona and C. Blanpain Naturehttp://dx.doi.org/10.1038/nature24753; 2017). For example, normal regeneration of the epidermis is directed by only a few stem-cell clones that can self-renew.

Source: http://www.nature.com/

Cancer: How To Shrink Tumors

Math, biology and nanotechnology are becoming strange, yet effective bed-fellows in the fight against cancer treatment resistance. Researchers at the University of Waterloo and Harvard Medical School have engineered a revolutionary new approach to cancer treatment that pits a lethal combination of drugs together into a single nanoparticle. Their work, published online on June 3, 2016 in the  journal ACS Nano, finds a new method of shrinking tumors and prevents resistance in aggressive cancers by activating two drugs within the same cell at the same time. Every year thousands of patients die from recurrent cancers that have become resistant to therapy, resulting in one of the greatest unsolved challenges in cancer treatment. By tracking the fate of individual cancer cells under pressure of chemotherapy, biologists and bioengineers at Harvard Medical School studied a network of signals and molecular pathways that allow the cells to generate resistance over the course of treatment.

anti cancer nanoparticle

Using this information, a team of applied mathematicians led by Professor Mohammad Kohandel at the University of Waterloo (Canada), developed a mathematical model that incorporated algorithms that define the phenotypic cell state transitions of cancer cells in real-time while under attack by an anticancer agent. The mathematical simulations enabled them to define the exact molecular behavior and pathway of signals, which allow cancer cells to survive treatment over time.

They discovered that the PI3K/AKT kinase, which is often over-activated in cancers, enables cells to undergo a resistance program when pressured with the cytotoxic chemotherapy known as Taxanes, which are conventionally used to treat aggressive breast cancers. This revolutionary window into the life of a cell reveals that vulnerabilities to small molecule PI3K/AKT kinase inhibitors exist, and can be targeted if they are applied in the right sequence with combinations of other drugs.

Previously theories of drug resistance have relied on the hypothesis that only certain, “privileged” cells can overcome therapy. The mathematical simulations demonstrate that, under the right conditions and signaling events, any cell can develop a resistance program.

Only recently have we begun to appreciate how important mathematics and physics are to understanding the biology and evolution of cancer,” said Professor Kohandel. “In fact, there is now increasing synergy between these disciplines, and we are beginning to appreciate how critical this information can be to create the right recipes to treat cancer.”

Source: https://uwaterloo.ca/

How To Fight Septic Shock, Save Millions

Last year, a Wyss Institute (Harvard) team of scientists described the development of a new device to treat sepsis that works by mimicking our spleen. It cleanses pathogens and toxins from blood circulating through a dialysis-like circuit. Now, the Wyss Institute team has developed an improved device that synergizes with conventional antibiotic therapies and that has been streamlined to better position it for near-term translation to the clinic. Sepsis is a common and frequently fatal medical complication that can occur when a person’s body attempts to fight off serious infection. Resulting widespread inflammation can cause organs to shut down, blood pressure to drop, and the heart to weaken. This can lead to septic shock, and more than 30 percent of septic patients in the United States eventually die. In most cases, the pathogen responsible for triggering the septic condition is never pinpointed, so clinicians blindly prescribe an antibiotic course in a blanket attempt to stave off infectious bacteria and halt the body’s dangerous inflammatory response.

But sepsis can be caused by a wide-ranging variety of pathogens that are not susceptible to antibiotics, including viruses, fungi and parasites. What’s more, even when antibiotics are effective at killing invading bacteria, the dead pathogens fragment and release toxins into the patient’s bloodstream.
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The inflammatory cascade that leads to sepsis is triggered by pathogens, and specifically by the toxins they release,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who leads the Wyss team developing the device and is the Judah Folkman Professor of Vascular Biology at Boston Children’s Hospital and Harvard Medical School and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Science. “Thus, the most effective strategy is to treat with the best antibiotics you can muster, while also removing the toxins and remaining pathogens from the patient’s blood as quickly as possible.”

The Wyss team’s blood-cleansing approach can be administered quickly, even without identifying the infectious agent. This is because it uses the Wyss Institute‘s proprietary pathogen-capturing agent, FcMBL, that binds all types of live and dead infectious microbes, including bacteria, fungi, viruses, as well as toxins they release. FcMBL is a genetically engineered blood protein inspired by a naturally-occurring human molecule called Mannose Binding Lectin (MBL), which is found in the innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen.

The findings are described in the October volume 67 of Biomaterials.

Source: http://wyss.harvard.edu/
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http://www.reuters.com/

NanoDrones Destroy Fat In Arteries

Nanometer-sized “drones” will deliver a special type of healing molecule to fat deposits in arteries. This is new approach to prevent heart attacks caused by atherosclerosis, according to a study in pre-clinical models by scientists at Brigham and Women’s Hospital (BWH) and Columbia University Medical Center.

Although current treatments have reduced the number of deaths from atherosclerosis-related disease, atherosclerosis remains a dangerous health problem: Atherosclerosis of the coronary arteries is the #1 killer of women and men in the U.S., resulting in one out of every four deaths. In the study, targeted biodegradable nanodrones’ that delivered a special type of drug that promotes healing (‘resolution‘) successfully restructured atherosclerotic plaques in mice to make them more stable. This remodeling of the plaque environment would be predicted in humans to block plaque rupture and thrombosis and thereby prevent heart attacks and strokes.
nanodronesNanometer-sized ‘drones’ that deliver a special type of healing molecule to fat deposits in arteries could become a new way to prevent heart attacks caused by atherosclerosis
This is the first example of a targeted nanoparticle technology that reduces atherosclerosis in an animal model,” said co-senior author Omid Farokhzad, MD, associate professor and director of the Laboratory of Nanomedicine and Biomaterials at BWH and Harvard Medical School (HMS). “Years of research and collaboration have culminated in our ability to use nanotechnology to resolve inflammation, remodel and stabilize plaques in a model of advanced atherosclerosis.”

These findings are published in the February 18th online issue of Science Translational Medicine.
Source: http://www.brighamandwomens.org/

How To Develop Stronger Artificial Hearts

Ali Khademhosseini,, a researcher from the Brigham and Women’s Hospital, a division of Harvard Medical School, has created ultra-thin cardiac patches. Now medicine is a step closer to durable, high-functioning artificial tissues that could be used to repair damaged hearts and other organs.

artificial-heart
The cardiac tissue patches utilize a hydrogel scaffolding reinforced by nanomaterials called carbon nanotubes. To create the patches, the researchers seeded neonatal rat heart muscle tissue onto carbon nanotube-infused hydrogels.
Source: http://researchfaculty.brighamandwomens.org/
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http://phys.org/