Granulomatosis with polyangiitis (GPA) is a form of autoimmune vasculitis that is associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). In this episode, Véronique Witko-Sarsat, Nathalie Thieblemont, and Katherine Martin discuss their work, which shows that PR3 expression is enhanced on the surface of apoptotic neutrophils from GPA patients. PR3-expressing apoptotic neutrophils were found to promote pro-inflammatory responses and prevent the development of regulatory T cells. Moreover, the authors show that this immune dysregulation was also present in GPA patients. Together, the results of this study provide important insight into the pathogenesis of GPA.
Helen Hobbs is an investigator of the Howard Hughes Medical Institute and a professor of Internal Medicine and Molecular Genetics at the University of Texas Southwestern Medical Center. Additionally, she is the director of the Dallas Heart Study, a longitudinal, multiethnic population-based study of over 6,000 adults that aims to identify genetic, protein, and imaging biomarkers for early detection of cardiovascular disease as well as social, behavioral, and environmental factors that contribute to cardiovascular disease risk. By studying outliers in this population, Dr. Hobbs identified a genetic defect in PCSK9 that is responsible for low plasma LDL levels. In an interview with JCI Editor-at-Large Ushma Neill, Dr. Hobbs discusses her early scientific training at Parkland Memorial Hospital in Dallas under the direction of Donald Seldin, who guided her to scientific bench training. She also discusses the initiation of the Dallas Heart Study and the development of a therapeutic inhibitor of PCSK9 for lowering LDL.
Editor-at-Large Ushma Neill interviews Rudolf Jaenisch of MIT’s Whitehead Institute. Dr. Jaenisch created the first transgenic mice and conducted the first experiment demonstrating that therapeutic cloning could correct a genetic defect. Additionally, Jaenisch has been at the forefront of research on induced pluripotent stem cells and has shown that these cells can correct sickle cell anemia and Parkinson disease in rodents. In this interview, Jaenisch discusses his work as a postdoctoral fellow in Arnold Levine’s lab studying DNA replication with the tumor virus SV40, which led to his collaboration with developmental geneticist Beatrice Mintz. Additionally, Jaenisch discusses adoption of new methods and technologies to address interesting questions in genetics as well as the application of these technologies to humans.
Retinitis pigmentosa (RP) is hereditary retinal degenerative disease that is characterized by progressive loss of photoreceptor function. In human trials, gene therapy has been shown to improve vision; however, this benefit has not been sustainable. It is not clear if the lack of long-term benefit is due to the advanced stage of the disease at the time of therapy or due to inefficient delivery of the functional gene. In this episode, Stephen Chang and Susanne Koch discuss the development of a murine RP model that allows induction of the corrected gene at various stages of disease. The results of their study indicate that gene therapy can treat RP even at advanced stages and that future studies should focus on improving gene delivery.
Epigenetic modifications, such as histone acetylation, are dysregualted in Alzheimer’s disease (AD) and other neurodegenerative disorders, resulting altered patterns of neuronal gene expression and cognitive decline. In this episode, Eva Benito-Garagorri reveals that the small molecule histone-deacetylase (HDAC) suberoylanilide hydroxamic acid (SAHA) improves cognitive function and restores neuronal gene expression patterns in murine models of aging and neurodegeneration. Importantly, oral administration of SAHA provided these beneficial effects in neurons and did not affect non-neuronal cells. The results of this study suggest that SAHA should be further explored for the treatment of neurodegenerative disorders and age-related cognitive decline.