Hemophilia refers to a class of genetic disorders characterized by the impairment of blood clotting or coagulation due to the lack of clotting factors normally produced by the liver. Hemophilia type A, for example, results from the deficiency of Clotting Factor VIII while Hemophilia type B results from the lack of Clotting Factor IX. In a recent study published in the New England Journal of Medicine, British researchers at University College London Cancer Institute in collaboration with St. Jude Children’s Research Hospital successfully treated six severe Hemophilia B patients by introducing into them a gene coding for Clotting Factor IX. While past clinical trials using gene therapy were not able to produce lasting expression of clotting factors, this current study shows expression lasting for at least a year. Further, animal models using the same methods have shown genetic expression for up to ten years.
In their study, the scientists used a viral vector (a virus incapacitated of reproduction and infectivity) to carry DNA containing code for Clotting Factor IX. This vector specifically targets the liver where it initiates the production of Clotting Factor IX. All six patients taking part in this study originally produced less than 1% of the normal expected levels of Clotting Factor IX. After a year into the gene therapy trial, the patients were all producing 2 – 12% of the normal levels of Clotting Factor IX (with higher dosages of the viral cocktail corresponding to higher production of Clotting Factor IX). While this appears minute, the research is making steady progress. Perhaps once the gene therapy methods reach optimal potency, the scientists can transition to studying the more prevalent Hemophilia A which requires delivery of a larger gene (for Clotting Factor VIII).
The current treatment for hemophilia B involves injecting clotting factor IX concentrate into patients with the disease. The cost for this can range anywhere from $150,000 to $300,000 a year depending on the frequency of injections needed by the patient. The proposed gene therapy, in addition to its efficacy, would bring down costs for treatment to around $30,000 per patient, since a single treatment would last at least a year as the study has shown. The researchers involved in this study explain their findings below:
As published earlier this month in the peer-reviewed journal Public Library of Science (PLoS) Pathogens, researchers have discovered that fatal prion diseases such as Bovine spongiform encephalopathy (a.k.a. Mad Cow Disease) show signs of destroying a particular protein up to seven months prior to infection. This protein called shadoo is found in lower concentrations as the early stage of prion disease unfolds in an infected brain.
“This is telling us there is a process within the disease that we were previously unaware of, a process that is happening before the infected animals are getting sick. It’s telling us that the brain cells are more active in defending themselves than we thought. The brain cells are in fact trying to get rid of the prion protein, and as a consequence, this bystander shadoo protein is being destroyed unintentionally,” says lead author and co-principal investigator, David Westaway.
Westaway, who works for both the Centre for Prions and Protein Folding Diseases and the Division of Neurology at the University of Alberta, collaborated with several other researchers from scientific departments in Canada, the US and Germany to make this discovery. A thorough study of how the brain cells attempt to fend off the prion protein may lead to scientific advancements in aiding this process to better protect the animal hosts and reduce the fatalities in such prion diseases.
Co-principal investigator George Carlson of the McLaughlin Research Institute in Montana noted that increasing the amount of shadoo protein in laboratory models did nothing to deter the course of prion disease, meaning the role of shadoo protein itself is not yet fully understood. Nonetheless, the only reproducible sign of prion disease thus far is reduction in the levels of shadoo protein.
Researchers at the University of California San Diego School of Medicine, in collaboration with Australian colleagues, have genetically modified zebrafish to serve as a model for atherosclerosis, a disorder where arterial walls are hardened from the buildup of LDL (or bad cholesterol) and other substances that form rigid structures called plaques. Atherosclerosis is a dangerous condition that can lead to blood clots, heart attacks or strokes. In a recent press release summarizing their methods and findings, the team outlines the advantages of the zebrafish model.
Young zebrafish are transparent, allowing researchers to literally see and capture the effects of dietary changes and the efficacy of different drugs on plaque formation. To clarify the results, an antibody that recognizes oxidized LDL conjugated with green fluorescent protein was introduced into the zebrafish genome, inducing them to create fluorescent antibodies that would bind to the bad cholesterol and make them visible as in the image above (top right).
Using appropriate imaging techniques, the team observed that treating a fish with an antioxidant drug proved therapeutically equivalent to switching the fish to a low cholesterol diet. Results showed up in just ten days, compared to the nearly six months required to complete similar experiments in mice, marking an order of magnitude improvement in the time required to conduct such studies.
“I see this cholesterol-fed, transgenic zebrafish model as a novel way to study early vascular lipid accumulation and lipoprotein oxidation, the processes that lead to heart disease in humans,” said team leader Yuri Miller, MD, PhD. “Since it is relatively easy and cost-effective to establish and maintain new transgenic zebrafish lines, this offers an in-vivo test for new antioxidants and other drug candidates that could affect development of human atherosclerosis.”
Researchers from the National Cancer Institute (NCI), under the umbrella of NIH and in conjunction with the Health Resources and Services Administration, evaluated medical data from 175,700 transplant recipients and discovered evidence that tied organ transplantation to 32 different types of cancer.
Lead author Eric A. Engels, M.D. works in the Division of Cancer Epidemiology and Genetics of the Infections and Immunoepidemiology Branch at NCI. Regarding the reasoning for such a disturbing trend, he had the following to say:
“While transplantation is a life-saving therapy for patients with end-stage organ disease, it also puts recipients at an increased risk for developing cancer, in part because of medications administered to suppress the immune system and prevent rejection of the organ. The cancer risk among transplant recipients resembles that of people with HIV infection, whose risk is elevated for infection-related cancers due to immunosuppression.”
Although it has been common knowledge that transplant recipients are at higher risk for developing cancer than the general populace, never before has such a large patient population or variety of organ types been scrutinized. Previous studies mostly focused on kidney transplants or screened for particular cancer types. The NCI study, on the other hand, surveyed 13 regional cancer registries over 21 years, and 175,700 patients who comprise 40% of the recipient population.
Such a representative sample allowed the study to make several observations about rarer cancer types, establish that a twofold overall increased risk of cancer exists among all U.S. transplant recipients, and link cancers to both infectious and non-infectious agents. Specifically, they found that the most common cancers among transplant recipients were non-Hodgkin lymphoma, lung cancer, liver cancer, and kidney cancer.
An interesting attribute of biomedical engineering is its constant evolution in conjuncture with theory. A previous article on this site describes the tissue engineering technique of cell sheet layering (pioneered in 2003). This technique has developed much since then, and several advances has been made by the same laboratory responsible for the original research.
As stated previously, one main challenge of cell sheet engineering is vascularization of three dimensional tissue constructs. The researchers at Tokyo Women’s Medical University have continued developing their technique, and have recently (2011) found a way for the cells in cell sheet layers to assist in their own vascularization. They found that creating a micropattern on the surface of thermoresponsive polymer culture dishes caused human fibroblast cells to align, altering their physical and biochemical action. Alignment is caused by intracellular receptors which bind to the cell’s environment and relay information about the culture surface back to the cell. This physical feedback has a powerful effect on the chemistry of the cell, and in this case causes human fibroblasts to release a protein known as VEGF (Vascular Endothelial Growth Factor). VEGF is widely recognized as the main activator in angiogenesis, and inducing its expression is a critical step forward in engineering vascular 3D tissue.
The presence of VEGF alone, however, is not enough to promote angiogenesis (though it is the first step in a complicated process). The biochemical environment of the body is extremely complex, so researchers must find ways to combine the correct cell types, growth factors, and mechanical stimuli to induce and maintain blood vessel growth in engineered tissues. Once this strategy matures, the implications are immense. Already, scientists have successfully fabricated many types of tissue at a basic level such as heart, lung, and neural tissue. Once it becomes possible to create fully vascularized tissues, the restrictions in place now will be greatly reduced, allowing for the development of much more complex tissue cultures such as fully functional, biologically engineered organs.
To learn more about cell sheet engineering, click here
UC Berkeley bioengineer, Seung-Wuk Lee, is working to harness genetically engineered viruses for the creation of microstructures and biomimetic materials (materials that imitate natural structures in the body such as that found in skin, teeth, and corneal tissue).
Last week, the National Science Foundation (NSF) held a webcast with Lee to discuss the new viral synthesis technology. As his team describes in their paper, self-templating (the concept of a molecule using itself as a template such that one molecule X serves as the positional template for the next molecule, also X), has not been thoroughly explored as a means of engineering synthetic materials. So, Lee’s team decided to create a simple, single-step technique to direct benign bacterial viruses called M13 phages to serve as building blocks for materials with diverse physical, optical and chemical properties. The M13 phage virus is commercially available, well-documented and easy to harvest after tuning of genetic structure for a specific purpose.
When these viruses are put to work in a controlled environment, they produce highly ordered structures. Variables such as the available surface of the glass substrate, concentration of viruses, and ionic concentrations all affect the type of structure produced. So far, Lee’s team has successfully created three categories of films.
“We strongly believe that our novel approach to constructing biomimetic ‘self-templated’, supramolecular structures closely mimics natural helical fiber assembly,” says Lee. “One important reason is that we not only mimicked the biological structures, but we also discovered structures that have not been seen in nature or the laboratory…”
Eventually, the biomimetic materials produced can be applied to various ends such as tissue replacement for patients. Admittedly, tissue engineering is already possible through other means, but what makes the viral method remarkable is the hands-off efficiency and simplicity of the whole process.
Below is a video of the technology being used to create a periodic texture:
