跳至主要内容

Researchers Discover New Inflammatory Disease

   NIH researchers report the discovery of a rare and sometimes lethal inflammatory disease – otulipenia – that primarily affects young children. They have also identified anti-inflammatory treatments that ease some of the patients’ symptoms: fever, skin rashes, diarrhea, joint pain, and overall failure to grow or thrive.

   



        Otulipenia is caused by the malfunction of OTULIN, a single gene on chromosome 5. When functioning properly, OTULIN regulates the development of new blood vessels and the mobilization of cells and proteins to fight infection. The researchers published their study (“Biallelic Hypomorphic Mutations in a Linear Deubiquitinase Define Otulipenia, an Early-onset Autoinflammatory Disease”) in PNAS.


At present, as the pathogenesis of inflammatory and immunological diseases is unclear, there are few effective therapeutic drugs available in clinical practice. In such a context, the appropriate preclinical research techniques and models are required to help companies and researchers further develop and evaluate new drugs. Our Preclinical Pharmacodynamics Department has been deeply involved in this field for years, developing reliable animal-based efficacy evaluation models aimed at different targets and pathways, thus facilitating the clinical transformation of new drugs.

   

        Contributing to the work were researchers from the National Human Genome Research Institute (NHGRI), the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, and the NIH Clinical Center, all part of NIH, along with their colleagues in Turkey and the U.K.

   

        “The results have been amazing and life changing for these children and their families,” said Daniel Kastner, M.D., Ph.D., co-author, NHGRI scientific director and head of NHGRI’s Inflammatory Disease Section. “We have achieved the important goal of helping these young patients and made progress in understanding the biological pathways and proteins that are important for the regulation of the immune system’s responses.”

   

        Otulipenia is one of several inflammatory diseases that occur when the immune system attacks the host’s own tissues. Inflammation is the body’s natural response to invading bacteria or viruses. The body releases chemicals that cause blood vessels to leak and tissues to swell in order to isolate a foreign substance from further contact with the body’s tissues. Inflammatory diseases affecting the whole body are caused by mutations in genes like OTULIN that are part of a person’s innate immunity.

   

        An international network of scientists studying inflammatory diseases identified four children from Pakistani and Turkish families with unexplained skin rashes and inflamed joints. NIH scientists then searched for disease-causing genes using next-generation DNA sequencing, technology that allows researchers to sequence DNA quickly and economically.

   

        Once they found that the OTULIN gene was abnormal in the sick children, they studied the immune pathway to understand the mechanisms of disease and to improve treatment of these patients. They discovered a problem in the processing of a small protein, ubiquitin, which is critical to the regulation of many other proteins in the body, including immune molecules. In the affected children, the inability to remove the ubiquitin proteins from various molecules resulted in an increased production of inflammatory cytokines.


   

        The researchers determined that the children with otulipenia might respond to drugs that turned off tumor necrosis factor (TNF), a chemical messenger involved in systemic inflammation. Inflammation subsided in the children who had been treated with TNF inhibitors, which are also used to treat chronic inflammatory diseases such as rheumatoid arthritis.

   

        “The malfunction in this protein has not been previously linked to clinical disorders of the human immune system,” said Ivona Aksentijevich, M.D., staff scientist in NHGRI’s Medical Genetics Branch and study co-author. “This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases.”

   

    This study, together with NIH’s previous identification of haploinsufficiency of A20 (HA20), suggests a new category of human inflammatory diseases caused by impaired ubiquitination, according to the researchers.

标签：

评论

发表评论

此博客中的热门博文

What is preclinical testing?

In the process of  preclinical testing  of a compound or biological agent into a drug, the compound involved must go through the testing phase. First, we need to identify potential targets that can treat the disease. Then, a variety of compounds or preparations are screened out. Any compound that has shown potential as a drug for the treatment of this disease needs to be tested for toxicity before clinical testing to reduce the possibility of injury. preclinical testing What is the basis of preclinical testing? According to US Food and Drug Administration (FDA) regulations, a series of tests are required before a new drug is approved for use. In the first stage, basic research determines a hypothetical target for the treatment of a certain disease, and then screens small molecules or biological compounds to discover any substance with the potential to treat the disease. Then, a  preclinical research  phase followed, before which, as described above, the potential toxicity of the compou
发表评论
阅读全文

Inventory of the three major in vitro pharmacokinetic research methods

  The metabolic properties of a compound are an essential factor in whether or not it can be used as a drug in the clinical setting, so pharmacokinetic studies of newly synthesized compounds are required in drug development. In vitro incubation with liver microsomes, recombinant CYP450 enzyme lines, and in vitro incubation with hepatocytes are some of the more common in vitro drug metabolism methods. 1. In vitro incubation method with liver microsomes The metabolic stability and metabolic phenotypes of candidate compounds in different species of liver microsomes are good predictors of the metabolic properties of compounds in vivo. They are practical tools for evaluating candidate compounds in the pre-development phase of drug development. Liver microsomes include rat liver microsomes, human liver microsomes, canine liver microsomes, monkey liver microsomes, and mouse liver microsomes. In in vitro incubation of the liver, microsomes are the "gold standard" for in vitro d
发表评论
阅读全文

Novel Parkinson’s Therapies Possible with New Mouse Model

Parkinson's disease (PD) is a neurodegenerative disorder that is marked by the accumulation of the protein, α-synuclein (αS), into clumps known as Lewy bodies, which diminish neural health. Now, researchers from Brigham and Women's Hospital (BWH) report the development of a mouse model to induce PD-like αS aggregation, leading to resting tremor and abnormal movement control. The mouse responds to L-DOPA, similarly to patients with PD. The team's study (“Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease”) on the use of this transgenic mouse model appears in  Neuron . “α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in PD. Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutati
发表评论
阅读全文