Corporate Banner
Satellite Banner
Immunology
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

NIH Scientists Identify Gene Linked to Fatal Inflammatory Disease in Children

Published: Friday, July 18, 2014
Last Updated: Friday, July 18, 2014
Bookmark and Share
Repurposed drugs may offer first potential therapy.

Investigators have identified a gene that underlies a very rare but devastating autoinflammatory condition in children. Several existing drugs have shown therapeutic potential in laboratory studies, and one is currently being studied in children with the disease, which the researchers named STING-associated vasculopathy with onset in infancy (SAVI).

The findings appeared online in the New England Journal of Medicine. The research was done at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 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,” said NIAMS Director Stephen I. Katz, M.D., Ph.D. “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.”

The senior author of the study, Raphaela Goldbach-Mansky, M.D., and the co-lead authors, Yin Liu, M.D., Ph.D., Adriana A. Jesus, M.D., Ph.D., and Bernadette Marrero, Ph.D., are in the NIAMS Translational Autoinflammatory Disease Section.

Autoinflammatory diseases are a class of conditions in which the immune system, seemingly unprovoked, 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.

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 the 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.

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.

The 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.

The 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.

Dr. Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in people with SAVI.

“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” said Dr. Goldbach-Mansky. “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.”

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.

The 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.”


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

HIV Control Through Treatment Durably Prevents Heterosexual Transmission of Virus
NIH-funded trial proves suppressive antiretroviral therapy for HIV-infected people effective in protecting uninfected partners.
Tuesday, July 21, 2015
Starting Antiretroviral Treatment Early Improves Outcomes for HIV-infected Individuals
NIH-funded trial results likely will impact global treatment guidelines.
Thursday, May 28, 2015
For Most Children with HIV and Low Immune Cell Count, Cells Rebound After Treatment
NIH-funded study finds T-cell level returns to normal with time.
Saturday, March 28, 2015
Strengthening the Immune System’s Fight Against Brain Cancer
NIH-funded research suggests novel way to improve vaccine efficacy in brain tumors.
Friday, March 20, 2015
Autoimmune Disease Super-Regulators Uncovered
Scientists discovered key genetic switches, called super-enhancers, involved in regulating the human immune system.
Tuesday, March 17, 2015
NIH Announces $41.5 Million in Funding for the Human Placenta Project
Better understanding of the placenta promises to improve the health of mothers and children.
Tuesday, March 03, 2015
NIH-funded Scientists Create Potential Long-acting HIV Therapeutic
New molecule also might prevent HIV infection.
Tuesday, February 24, 2015
Link Between Powerful Gene Regulatory Elements and Autoimmune Diseases Revealed
Findings point to potential drug targets.
Thursday, February 19, 2015
NIH-Sponsored HIV Vaccine Trial Launches In South Africa
Early-stage trial aims to build on RV144 results.
Thursday, February 19, 2015
Stem Cell Transplants May Halt Progression of Multiple Sclerosis
NIH-funded study yields encouraging early results.
Tuesday, December 30, 2014
Candidate H7N9 Avian Flu Vaccine Works Better With Adjuvant
Results of large NIH-sponsored trial demonstrate improved vaccine response when an adjuvant was used.
Wednesday, October 08, 2014
NIH Awards Seven New Vaccine Adjuvant Discovery Contracts
Total funding for these contracts reach approximately $70 million over five years.
Tuesday, October 07, 2014
NIH to Admit Patient Exposed to Ebola Virus for Observation
Ebola patients can be safely cared for at any hospital that follows CDC's infection control recommendations.
Wednesday, October 01, 2014
NIH Announces Network to Accelerate Medicines for Rheumatoid Arthritis and Lupus
Partnership includes support from industry and non-profits.
Friday, September 26, 2014
NIH-Led Scientists Discover HIV Antibody that Binds to Novel Target on Virus
The antibody, 35O22, prevents 62 percent of known HIV strains from infecting cells in the laboratory.
Friday, September 05, 2014
Scientific News
New Weapon in the Fight Against Blood Cancer
This strategy, which uses patients’ own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
Scientists Create CRISPR/Cas9 Knock-In Mutations in Human T Cells
In a project spearheaded by investigators at UC San Francisco, scientists have devised a new strategy to precisely modify human T cells using the genome-editing system known as CRISPR/Cas9.
Researchers Develop Vaccine that Protects Primates Against Ebola
A collaborative team from The University of Texas Medical Branch at Galveston and the National Institutes of Health have developed an inhalable vaccine that protects primates against Ebola.
Universal Flu Vaccine in the Works
A new study has demonstrated a potential strategy for developing a flu vaccine with potent, broad protection.
Immunotherapy Shows Promise for Myeloma
A strategy, which uses patients’ own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
Immune System 'On Switch' Breakthrough Could Lead to Targeted Drugs
A crucial 'on switch' that boosts the body's defenses against infections has been successfully identified in new scientific research.
HIV Control Through Treatment Durably Prevents Heterosexual Transmission of Virus
NIH-funded trial proves suppressive antiretroviral therapy for HIV-infected people effective in protecting uninfected partners.
Adaptimmune's Novel Cancer Therapeutics Show Positive Clinical Trial Results
The company has announced that positive data from its Phase I/II study of its affinity enhanced T-cell receptor (TCR) therapeutic targeting the NY-ESO-1 cancer antigen in patients with multiple myeloma has been published.
Adaptimmune’s NY-ESO-1 TCR-engineered T-Cells Demonstrate Durable Persistence
Study has been published in Nature Medicine.
Iron Regulators Join War on Pathogens
Iron regulatory proteins (IRPs) play an important role in the body’s immune system.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!