Platform for screening and evaluating small molecules as potential drugs for various human genetic disorders uses human pluripotent stem cells as a model system.
By JUDY SIEGEL-ITZKOVICHAnimals [Illustrative](photo credit: INGIMAGE)
Animals are often tested and sacrificed as humanely as possible to study novel methods for fighting various diseases, but this approach suffers from various limitations. For example, numerous developmental diseases can’t be studied using animal models. But now, Yissum – the Hebrew University research and development company – has introduced a new technology for large-scale screening and testing of rare (“orphan” diseases) without using animal models.The platform for screening and evaluating small molecules as potential drugs for various human genetic disorders was developed by Prof. Nissim Benvenisty, director of HU’s Azrieli Center for Stem Cells and Genetic Research. It uses human pluripotent stem cells (hPSCs) as a model system that overcomes several limitations inherent to animal models.As part of the novel approach, Benvenisty’s Center has generated hPSCs representing human genetic disorders such as Fragile X syndrome or Down syndrome, as well as other genetic conditions such as some types of cancers or hereditary diabetes. The research team has so far developed 15 disease cell models for 13 genetic disorders, which can serve not only to understand the molecular basis underlying these diseases but also as platforms for screening small molecules to treat these disorders. In addition, since the cellular models are derived from human cells, they can also serve to validate potential drugs intended for the treatment of human developmental genetic disorders.Yissum CEO Ya’acov Michlin commented, “The new disease model system developed by Prof. Benvenisty offers a complementary approach that can address many of the hurdles inherent to animal models. We are certain that this novel method will have a significant impact on drug screening and development, and Yissum is currently looking for partners in order to further advance this promising approach.”Animal models are an important step in the research and development of many drugs, but they often fall short due to various limitations. This cellular system, based on human stem cells, enable – for example – cost-effective, high-throughput screening of small molecules as potential drugs for a variety of genetic and other conditions, screening which is not possible using many animal models.“The ability to manipulate the genome of these cells to emulate various genetic diseases offers an extensive potential to study, understand and develop new therapies for many complex diseases with an underlying genetic basis,” Michlin explained.INFLAMMATION AND INFECTIONS A “smart” drug that mimics a natural process that occurs during inflammation in the body has been developed by scientists at Beersheba’s Ben-Gurion University of the Negev and the University of Colorado. The dynamic drug is “attentive” to the degree of inflammation, wrote the researchers in the recent edition of the Journal of Immunology.The development is important since inhibition of inflammation in a non-specific manner reduces humans’ natural ability to fight infections. This is a common side-effect of anti-inflammatory biologic therapeutics.When a non-specific agent is used, any patient who suffers from local inflammation might then be exposed to opportunistic infections at distant sites, such as lungs, risking, for example, tuberculosis. This risk is mainly of concern to immunosuppressed patients, as well as older patients and patients undergoing chemotherapy as part of an anti-cancer treatment course, said Dr. Peleg Rider of the department of clinical biochemistry and pharmacology in BGU’s Faculty of Health Sciences.
He and his colleagues described in the journal a novel creative development of an anti-inflammatory engineered protein. While it is injected as a non-active drug, excessive inflammation will activate it, the researchers said. Most other anti-inflammatory agents do indeed effectively inhibit inflammatory processes, yet in a non-specific manner, and in areas that include sites of necessary normal inflammatory homeostasis (a situation in which variables are regulated so internal conditions remain stable and relatively constant).The beauty of this invention lies in the use of a known natural biological code,” Said Rider. “We mimicked a natural process that occurs during inflammation. The protein is actually a chimera comprised of two domains, both originating from the potent inflammatory cytokine family of IL-1. The first part of the protein holds the functional part of the molecule inactive, as occurs in normal living cells, and is connected to a potent natural inhibitor of IL-1. Upon encounter with inflammatory enzymes, the molecule is cleaved and the functional part becomes active,” he added.Rider, along with BGU’s Dr. Eli Lewis and Colorado Prof. Charles Dinarello showed in a mouse model of local inflammation that leukocytes, which infiltrate inflammatory sites, indeed activate the chimeric protein.This, in turn, reduces local inflammation. The activation of the protein correlated with the amount of inflammatory stimuli. Thus, a point that is highly relevant to clinical practice arises, according to which upon resolution of inflammation, the activation of the protein is also reduced, and side-effects are avoided. The new chimeric molecule is protected by patent, owned by BGN Technologies, the technology transfer office of Ben-Gurion University, and by the University of Colorado.