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Welcome to The Visible Embryo, a comprehensive educational resource on human development from conception to birth.

The Visible Embryo provides visual references for changes in fetal development throughout pregnancy and can be navigated via fetal development or maternal changes.

The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo. Initally designed to evaluate the internet as a teaching tool for first year medical students, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than one million visitors each month.

Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Home | Pregnancy Timeline | News Alerts |News Archive July 25, 2014

Blood vessels (yellow outline) of children with SAVI become inflamed, indicated in red.
Image: Manfred Boehm, M.D., National Heart, Lung, and Blood Institute.

 






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Gene link to fatal child inflammatory disease SAVI

Repurposed drugs may offer the first potential therapy to a very rare but devastating autoinflammatory disease in children.

National Institutes of Health (NIH) scientists have found a gene link to a devestating childhood  disease that kills children. Several existing drugs have shown therapeutic potential in laboratory studies, and one is currently being studied in children with the disease, which researchers named STING-associated vasculopathy with onset in infancy — or SAVI.

Their findings appear in the New England Journal of Medicine. Research was conducted at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health.


"Not only do these discoveries have profound implications for children with SAVI, but they could have a broader impact by helping us to understand other, more common inflammatory conditions. Diseases such as lupus share some characteristics with SAVI, so this work may lead to novel insights and possibly new treatments for these debilitating conditions, as well."

Stephen I. Katz, MD, PhD, director NIAMS


In 2004, Dr. Goldbach-Mansky was called upon to advise on a patient with a baffling problem—a 10-year-old girl with signs of systemic inflammation, especially in her blood vessels, who had not responded to any of the medications her doctors had used to treat her.

She had blistering rashes on her fingers, toes, ears, nose and cheeks, and had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.


Autoinflammatory diseases are a class of conditions in which the immune system, seemingly without being provoked, becomes activated and triggers inflammation.

Normally, the inflammatory response helps quell infections, but the prolonged inflammation that occurs in these diseases can damage the body.


By 2010, Dr. Goldbach-Mansky had seen two other patients with the same symptoms. She suspected that all three had the same disease, and that it was caused by a genetic defect that arose in the children themselves, rather than having been inherited from their parents, who were not affected. Her hunch suggested a strategy for identifying the genetic defect.


By comparing the DNA of an affected child with the DNA of the child's parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

DNA comparison revealed a novel mutation in a gene that encodes a protein called STING, a known signaling molecule whose activation leads to production of interferon, a key immune regulator. When overproduced, however, interferon can trigger inflammation.


"Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling," said Dr. Goldbach-Mansky. When the researchers tested the DNA of five other patients with similar symptoms, they found mutations in the same gene, confirming STING's role in the disease. The excessive inflammation observed in patients, along with other evidence of interferon pathway activation, indicated that the mutations in STING boosted the protein's activity.

Interferon normally works to restrict an invading pathogen's ability to replicate by triggering a function that stimulates immune cells. But prolonged activation of the pathway leads to chronic inflammation and damage to tissues and organs. Researchers found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by the disease.


"When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal. But because SAVI is caused by a single gene defect and interferon has such a strong role, I'm optimistic that we'll be able to target the pathway and potentially make a huge difference in the lives of these children."

Dr. Goldbach-Mansky


Dr. Goldbach-Mansky's team next looked for ways to dampen the inflammatory response in people with SAVI. Several drugs—tofacitinib, ruxolitinib and baricitinib—are known to work by blocking the interferon pathway, so the researchers reasoned that these medicines might be effective in people with SAVI, as well. When they tested the effect of the drugs on SAVI patients' blood cells in the lab, they saw a marked reduction in interferon-pathway activation.


Researchers are now enrolling SAVI patients in an expanded access program, also known as a compassionate use protocol.

Compassionate use protocols allow doctors to give investigational medicines to patients with serious diseases or conditions for which there is no comparable or satisfactory alternative therapy to treat the patient's disease or condition.


In future work, Dr. Goldbach-Mansky's team will further delve into STING's exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.

"These mutations help us to understand the disease, but they also give us the rare opportunity to study the biology of the STING-mediated immune response," said Dr. Liu. "We don't really understand how STING is activated or how the signal gets passed on to downstream molecules, but this work will help advance our understanding of this critically important pathway and its impact on other diseases."

Article Introduction
Studies involving children with monogenic autoinflammatory disease have provided insights into the regulation of key proinflammatory cytokine pathways and their role in causing systemic and organ-specific inflammation.1,2 We studied six patients who presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks, and ears that progressed to acral necrosis in most of the patients and did not respond to therapy. A mixed histologic pattern was observed, consisting of a prominent dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels. Three of the patients had severe interstitial lung disease.

Although many of the genetically defined autoinflammatory diseases are associated with increased interleukin-1 signaling and have a clinical response to interleukin-1 inhibition,2 interleukin-1–inhibiting therapy was ineffective in one of the patients. A prominent interferon-response-gene signature in the peripheral blood of this participant suggested interferon dysregulation similar to that seen in other genetically defined inflammatory syndromes, including the Aicardi–Goutières syndrome,3,4 an early-onset inflammatory encephalopathy, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE),5,6 a proteasome-associated autoinflammatory syndrome with proposed interferon-mediated pathologic features.7,8 We detected autosomal dominant mutations in TMEM173, the gene encoding the stimulator of interferon genes (STING), in the six children we assessed, who presented with a clinical syndrome we have called STING-associated vasculopathy with onset in infancy (SAVI).

This work was supported by the NIAMS intramural program under project number ZIAAR041138.

In addition to NIAMS, this research was supported by the National Cancer Institute; the National Heart, Lung, and Blood Institute; the NIH Department of Laboratory Medicine; the National Human Genome Research Institute; the NIH Department of Radiology and Imaging Services; the National Institute on Deafness and Other Communication Disorders; the National Institute of Allergy and Infectious Diseases; Dalhousie University, Halifax, Nova Scotia; RWTH Aachen University, Aachen, Germany; University Hospital of Muenster, Germany; Walter Reed National Military Medical Center, Bethesda, Maryland; Luis Calvo Mackenna Hospital, Santiago, Chile; Merck Research Laboratories, Boston; Northwestern University Feinberg School of Medicine, Chicago.

For more information on the trial enrolling SAVI patients, visit the following entry in the NIH clinical trials registry: NCT01724580.

Liu Y, de Jesus A, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, et. al. Activated STING in a Vascular and Pulmonary Syndrome. N Engl J Med. 2014. DOI: 10.1056/NEJMoa1312625.

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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