Genetic Insights in Autoimmune Diseases

Enzyme engineered by Yale researchers prevented lupus in mice and shows promise for patients with the disease. June 20, 2024. Excerpt: An enzyme-based treatment developed by Yale researchers mitigated autoimmunity and reduced death rates in genetic and non-genetic mouse lupus models, a new study reveals. The findings, published June 17 in the journal JCI Insight, represent a significant advancement in autoimmune disease therapeutics. Lupus is a chronic autoimmune disease that can cause inflammation and pain in any part of the body. Direct link to recently published research available in enclosed announcement. Note: “Although lupus was recently recognized as among the leading causes of death in young females in the U.S., we don’t really understand what causes the disease, which affects up to 1.5 million Americans,” said Dr. Demetrios Braddock, associate professor of pathology at Yale School of Medicine and lead author of the study. “We were interested in an ultra-rare form of lupus reported in only 40 patients worldwide who lacked an enzyme called DNAse1L3. All children without the enzyme developed lupus, we thought it could tell us about both disease mechanisms and new therapies.” Weekly doses of the long-acting enzyme — was engineered to replicate the activity of DNAse1L3 and be absorbed and used by the body — prevented autoimmunity from developing in a mouse model of genetic lupus for a year, essentially halting lupus development. When dosing started after the initiation of the disease, the enzyme reduced death rates. Although initially conceived for a rare pediatric population, the therapeutic — which was developed in the Braddock lab by lead scientist Paul Stabach — may also be effective in many more patients with lupus. This includes an estimated 35,000 patients with a pathogenic variant of DNAse1L3 that reduces the enzyme’s activity by about 80%. It also includes patients with lupus who have autoantibodies that neutralize DNAse1L3, which were characterized in the laboratory of Dr. Felipe Andrade at Johns Hopkins University in 2023. Andrade is co-author of the new study. “We recently became aware about one-third of patients with lupus have autoantibodies that block the function of DNAse1L3, mirroring patients who were born without the enzyme,” Andrade said. “Patients with antibodies to DNAse1L3 exhibited a more severe form of lupus with significant damage to organ systems, such as the kidneys. Although these patients may benefit from DNAse1L3 replacement therapy, the presence of autoantibodies precludes this option.” Addition: Refer to earlier published research discussing global incidence of systemic lupus erythematosus in individuals of Asian, Black, Hispanic and Indigenous ethnicity/race via Pub Med Central NIH Rheumatology (Oxford). 2023 Apr; 62(Suppl 1): i4–i9. The global epidemiology of SLE: narrowing the knowledge gaps

Last week ROME Therapeutics reported that their pioneering drug, RPT-A, has shown promising results in combating autoimmune diseases like lupus. The drug targets a specific segment of our DNA once considered "junk" – the dark genome. This part of the genome, making up over 98% of our DNA, plays a crucial role in regulating gene expression. RPT-A focuses on inhibiting Long Interspersed Element-1 (LINE-1), a retrotransposon known for its ability to move around the genome, affecting gene expression and that may trigger autoimmune diseases by activating type I interferons -inflammatory cytokines that are part of our innate immune response but are problematic in autoimmune conditions like lupus. The efficacy of RPT-A was demonstrated in mouse models of autoimmune disease, showing a reduction in autoantibodies and inflammation. Furthermore, studies on human cells revealed that LINE-1 stimulation inhibited type I interferon production, bolstering the case for RPT-A as a novel therapeutic approach. These results exemplify the incredible potential of exploring underutilized areas of our genome for therapeutic innovation and could be the beginning of a new era in personalized medicine, where understanding and manipulating specific genetic elements could lead to more targeted and effective treatments. Learn more here: https://lnkd.in/e3XPX3BU #AutoimmuneResearch #Genomics #BiotechInnovation #LupusTreatment #RomeTherapeutics

Mechanism of autoimmune link in muscular diseases Myotonic dystrophy 2 (DM2) is a form of muscular dystrophy, a disease that leads to progressive muscle degeneration. It is caused by the expansion of a repetitive DNA sequence containing multiple CCTG bases in the CNBP gene. In general, the sequence of nucleobases in the DNA carries the genetic information. Patients suffer from muscle weakness that is more pronounced in the area of the muscles close to the trunk, as well as sustained muscle stiffness and pain. In initial studies, the research team observed that patients with DM2 suffer more from autoimmune diseases with an increased production of antibodies in the blood than the general population. However, the underlying mechanism for these symptoms was previously unknown. The team showed that in the cells of DM2 patients, the DNA repeats (CCTG)n are translated into toxic nonsense proteins. Their formation leads to a chronic form of stress of endoplasmic reticulum (ER), a branched duct system as an extension of the nuclear membrane, which is where many proteins are folded. This ER Stress causes, in turn, chronic damage to the mitochondria, the energy powerhouse of the cells. These "stressed mitochondria" release small amounts of DNA within the cell, which are then recognized as a danger signal by the innate immune system. This is because cGAMP synthase (cGAS), an important innate immune receptor for DNA, recognizes this mitochondrial DNA and thus triggers an alarm state in the host by inducing release of the key antiviral mediator, type I interferon. #ScienceMission #ScienceNewhighlights https://lnkd.in/gTPkqRn7