IFNAR-1

Individuals with Down syndrome have less-frequent viral infections, but when present, these infections lead to more severe disease. New findings show that this is caused by increased expression of an antiviral cytokine type I interferon (IFN-I), which is partially coded for by chromosome 21. Elevated IFN-I levels lead to hyperactivity of the immune response initially, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in the viral attack. Individuals with Down syndrome have less-frequent viral infections, but when present, these infections lead to more severe disease. New findings publishing on October 14 in the journal Immunity show that this is caused by increased expression of an antiviral cytokine type I interferon (IFN-I), which is partially coded for by chromosome 21. Elevated IFN-I levels lead to hyperactivity of the immune response initially, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in the viral attack. "Usually too much inflammation means autoimmune disease, and immune suppression usually means susceptibility to infections," says senior study author Dusan Bogunovic of the Icahn School of Medicine at Mount Sinai. "What is unusual is that individuals with Down syndrome are both inflamed and immunosuppressed, a paradox of sorts. Here, we discovered how this is possible." Down syndrome is typically caused by triplication of chromosome 21. This syndrome affects multiple organ systems, causing a mixed clinical presentation that includes intellectual disability, developmental delays, congenital heart and gastrointestinal abnormalities, and Alzheimer's disease in older individuals. Recently, it has become clear that atypical antiviral responses are another important feature of Down syndrome. Increased rates of hospitalization of people with Down syndrome have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus (SARS-CoV-2) infections. While people with Down syndrome show clear signs of immune disturbance, it has yet to be elucidated how a supernumerary chromosome 21 leads to dysregulation of viral defenses. To address this knowledge gap, the researchers compared fibroblasts and white blood cells derived from individuals with and without Down syndrome, at both the mRNA and protein levels. They focused on the potent antiviral cytokine IFN-I receptor subunits IFNAR1 and IFNAR2, which are located on chromosome 21. The researchers found that increased IFNAR2 expression was sufficient for the hypersensitivity to IFN-I observed in Down syndrome, independent of trisomy 21. But subsequently, the hyper-active IFN-I signaling cascade triggered excessive negative feedback via a protein called USP18, which is a potent IFNAR negative regulator. This process, in turn, suppressed further responses to IFN-I and antiviral responses. Taken together, the findings unveil oscillations of hyper- and hypo-responses to IFN-I in Down syndrome, predisposing to both lower incidence of viral disease and increased infection-related morbidity and mortality. "We have a lot more to do to completely understand the complexities of the immune system in Down syndrome," says first author Louise Malle of the Icahn School of Medicine at Mount Sinai. "We have here, in part, explained the susceptibility to severe viral disease, but this is only the tip of the iceberg."

Sarah Silbiger/Getty Images One of the tenets of “personalized medicine” is that medications will be tailored to individuals based on their personalized genetics. Last year, the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research approved 50 drugs. A new study found that 33, or 66% of them, were supported with genomic data. Specifically, the study “investigated the proportion of new approvals that can be retrospectively explained based on publicly available human genetic information by using a mix of systematic mapping and manual curation. “We concluded that for 33 out of 50 (66%) of the FDA-approved new drugs in 2021, the genes coding for their primary assigned targets, or for proteins that are known to physically interact with these targets, have been previously associated in some way with the indication for which the drug is approved or a closely related phenotype.” Genetic Data Not Always Clear-Cut The authors, affiliated with the Wellcome Sanger Institute in Cambridgeshire, U.K., note that the genetic data with certain drugs is not always clear-cut. They point to Bayer’s Kerendia (finerenone), a NR3C2 antagonist approved last year for chronic kidney disease (CKD), as an example of both the opportunities and challenges of “developing a therapeutic hypothesis based on genetic evidence.” Genome-wide association studies (GWAS) were conducted that suggested an intronic variant in NR3C2 is linked to microalbuminuria, an early indication of CKD. But leveraging the available genetic data to prioritize that as a target depends on identifying the mechanistic link between the variant being associated with that trait and NR3C2, as well as evaluating how relevant microalbuminuria is for CKD patients. Other targets don’t have direct genetic evidence but do interact physically or functionally with “a genetically implicated gene product.” The researchers cite AstraZeneca’s Saphnelo (anifrolumab), which was approved last year for moderate to severe systemic lupus erythematosus (SLE). The drug is an IFNAR1 antagonist. The authors said they did not find direct genetic evidence linking SLE and IFNAR1. However, missense variants in TYK2, a kinase that physically interacts with IFNAR1, have been associated with SLE. “Thus,” they write, “genetic associations with interacting partners can provide indirect evidence for a suitable target, and this example highlights the potential utility of pathway and network data to interpret human variation in the context of disease.” Oncology is increasingly an area where specific biomarkers of the disease are associated with maximizing drug efficacy. As a result, detailed tumor genome characterization is common. The authors point to four of the cancer drugs approved last year which were indicated for patients with lung or bile duct cancers harboring somatic variations in EGFR, KRAS or FGFR2. They describe Amgen’s Lumakras (sotorasib), which was specifically developed to treat patients whose non-small cell lung cancer contains a KRAS G12C mutation. But similar testing is also being conducted on rare Mendelian diseases, such as Sarepta Therapeutics’ Amondys 45 (casimersen), which was approved in 2021 for Duchenne muscular dystrophy (DMD) that is amenable to exon 45 skipping. This requires a clear genetic evaluation of the patient’s dystrophin gene to determine exactly which mutations they have to help decide which, if any, DMD drug is right for them. Retrospective Analysis can Fuel Further Research However, the authors write, “When broadening to all rare indications, we found no increased genetic support in the 26 approvals receiving the FDA’s orphan drug designation compared with non-orphan drugs.” The authors suggest that more analysis of how drug approvals are associated with genetic data is needed. “While genetics might not have influenced the decision-making behind some of the genetically supported approved drugs, the availability of such evidence can retrospectively help to understand the causal mechanisms behind their therapeutic efficacy or safety. In future, positive outcomes for genetically supported therapeutic strategies will need to be assessed rigorously to avoid the risk of confirmation bias.”

New test aims to identify patients that may benefit from precision treatment LOS ANGELES, June 9, 2022 /PRNewswire/ -- DxTerity Diagnostics today announced the commercial launch of their IFN-1 Test for patients with Systemic Lupus Erythematosus (SLE or lupus). The IFN-1 Test supports the advancement of precision medicine to improve the lives of patients living with lupus. DxTerity's test measures a key biomarker, Type-1 Interferon (IFN-1), an important indicator of SLE disease severity and prognosis. High IFN-1 levels have been shown to lead to higher likelihood of disease severity and an increased risk for the development of lupus nephritis in SLE patients. The DxTerity IFN-1 Test is the first commercial IFN-1 gene expression assay and is now available to order. Patients living with lupus can find it difficult to predict and interpret symptoms. Each person's experience is unique and not all patients respond to standard treatments. Disease symptoms and treatment failure may be the result of a person's specific genomic activity. The DxTerity IFN-1 Test measures the expression levels of 4 genes associated with IFN-1 activity and identifies a patient as IFN-1 high or low. This information can be used by a healthcare provider to guide treatment. Rheumatologists have long been faced with limited therapy options for lupus management. With the recent FDA approval and availability of the Type-1 Interferon receptor blocking therapy anifrolumab (Saphnelo®), lupus patients have a new and much needed treatment option. "We are excited to launch the DxTerity IFN-1 Test, the first available IFN-1 gene signature test to provide information regarding a person's unique genomic activity," said Bob Terbrueggen, Ph.D., Founder and CEO of DxTerity Diagnostics. "It is our mission to transform patient care by developing diagnostic tools that support a personalized approach to the treatment of immune-mediated disease." DxTerity IFN-1 Test Information Providers and patients can learn more about DxTerity's IFN-1 Test for Lupus by reading our informational brochure and visiting the DxTerity's website. About DxTerity DxTerity Diagnostics is an ISO 13485-certified genomics company with a CLIA-licensed, CAP-accredited laboratory based near Los Angeles, CA. DxTerity Diagnostics develops simple, fast, and affordable genomic tests for disease diagnosis and disease monitoring. For more information, please visit and follow us on Twitter, Instagram, Facebook, and LinkedIn. Contact DxTerity Diagnostics Inc. Name: Mark Gersh Phone: 310-537-7857 Email: [email protected] SOURCE DxTerity Diagnostics, Inc.