caspase 9

A new study in mice suggests experimental eye drops may be more effective than injections for treatment of retinal vein occlusion, a major cause of blindness. A new study suggests that eye drops developed by Columbia University researchers could be a more effective-and comfortable-therapy for a common eye disease currently treated with injections into the eye. Retinal vein occlusion (RVO), an eye disease that affects up to 2% of people over age 40, occurs when a vein in the eye's retina becomes blocked, leading to swelling in the eye, inflammation, damage to the retina, and vision loss. Standard therapy involves injecting into the eye a vascular endothelial growth factor inhibitor (anti-VEGF) that reduces swelling. The therapy can improve vision but patients with significant retinal damage due to impaired blood flow often have poor outcomes. "Anti-VEGF therapy has helped a lot of people with RVO, but the fear factor -- having to get a needle in the eye -- causes many people to delay treatment, which can lead to retinal damage," says Carol M. Troy, MD, PhD, professor of pathology & cell biology and of neurology at Columbia University Vagelos College of Physicians and Surgeons. "There's an opportunity to help more people with this disease that is a leading cause of blindness worldwide." The study found that an experimental eye drop treatment was twice as effective as the standard injection therapy at reducing swelling and improving blood flow within the retina of mice with RVO. The eye drops also prevented neurons (photoreceptors) in the retina from deteriorating and preserved visual function over time, whereas the standard injections had no effect on either. Eye drops target 'death enzyme' The eye drops contain an experimental drug that blocks caspase-9, an enzyme that triggers cell death, and was found by Troy's lab to be overactive in blood vessels injured by RVO. "We think the eye drops improve the health of blood vessels in the retina, which then decreases the toxic signaling that damages the retina's neurons and leads to vision loss," says Maria I. Avrutsky, PhD, the study's first author who conducted the research as a postdoc in the Troy lab. Future studies are aimed at preparing to test the eye drops in human clinical trials and identifying additional therapeutic targets. "Finding the root cause of RVO is the holy grail, but if we can at least provide better symptomatic relief that doesn't distress patients, it would be a really good start," Troy says. More information The study, "Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion," was published online in Frontiers of Neuroscience. All authors: Maria I. Avrutsky (Columbia, now at Character Biosciences), Claire W. Chen (Columbia), Jacqueline M. Lawson (Columbia), Scott J. Snipas (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA) Guy S. Salvesen (Sanford Burnham Prebys), and Carol M. Troy (Columbia). The study was supported by a sponsored research agreement with Opera Therapeutics and grants from the National Institutes of Health (R01NS091333 and T32EY013933) and the Department of Defense Army/Air Force. Carol Troy and Maria Avrutsky are inventors on patent applications filed by Columbia University related to the therapeutic use of caspase-9 inhibitors. Maria Avrutsky received consulting income from Opera Therapeutics.

THURSDAY, April 6, 2023 -- Chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells (GD2-CAR T cells) are feasible and safe for children with heavily pretreated neuroblastoma, according to a study published in the April 6 issue of the New England Journal of Medicine . Francesca Del Bufalo, M.D., from IRCCS Ospedale Pediatrico Bambino Gesù in Rome, and colleagues conducted a phase 1/2 clinical trial involving 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and one with a complete response at the end of first-line therapy) who received GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). The researchers observed no failure to generate GD2-CART01. In the phase 1 part of the trial, three dose levels were tested (3-, 6-, and 10x10 6 CAR-positive T cells/kg body weight), with no dose-limiting toxic effects reported. For the phase 2 part of the trial, the recommended dose was 10x10 6 CAR-positive T cells/kg. In 74 percent of patients, cytokine release syndrome occurred and was mild in all but one patient. The suicide gene was activated in one patient, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo; up to 30 months after infusion, they were detectable in peripheral blood in 26 of 27 patients. Overall response was 63 percent, with nine and eight patients having a complete and partial response, respectively. Three-year overall survival and event-free survival were 60 and 36 percent, respectively, among children receiving the recommended dose. "GD2-CART01 may induce sustained eradication of disease in a proportion of patients with relapsed or refractory neuroblastoma," the authors write. Bellicum Pharmaceuticals donated rimiducid for the trial. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted April 2023

Unity CEO Anirvan Ghosh, Ph.D./courtesy of Unity Biotechnology Senolytic therapies are, at this point, as revolutionary as checkpoint inhibitors but with broader effectiveness. This approach delays the onset of diseases of aging by removing senescent cells from the body, thus enabling people to remain healthier longer or to regain some degree of function lost to disease. Senolytics is a new field and most of the research is still in academic centers – most notably, the Mayo Clinic. Approval of any therapeutics is years – perhaps even a decade – away. Currently, there are many unknowns. Laura Niedernhofer, M.D., Ph.D., a senolytics pioneer and professor in the department of biochemistry, molecular biology and biophysics at the University of Minnesota, highlighted just a couple in an interview with BioSpace. Laura Niedernhofer, M.D., Ph.D “We’re at the stage where we don’t know – in humans – which cells senesce and when, so there would be concern if, for example, post-mitotic cells that can’t be replaced were suddenly eliminated by senolytics,” she said. “We also don’t know which senescent cells are the most disadvantageous.” On the flip side, “Senescent cells also have healthy properties. They play an important role in wound healing and other physiologic processes,” Niedernhofer said. “In a perfect world, you would be able to target senolytics to very specific lineages of senescent cells, but we know how hard that is to do in cancer, so I think it’s asking for a lot.” Translational Challenges Neuroscientist Anirvan Ghosh, Ph.D., CEO of Unity Biotechnology, first encountered senescent cells in the context of Alzheimer’s disease. “What caught my attention was evidence showing the accumulation of senescent cells in the aging brain,” he told BioSpace. “Non-neuronal cells in the brain provide various kinds of support functions, including helping synaptic functions, and they end up in a senescent state. I thought a dysfunction in some other population of cells may be driving some part of the disease.” Ghosh found the consistency of evidence across animals and systems compelling. “The fundamental observation was that in the context of aging in vertebrates, there is a big increase in the number of the cells that are non-dividing, metabolically active cells.” "We’re all carrying some burden of senescent cells…usually at a benign level, and it’s very likely contributing to the aging process. But, in certain stressed environments, the risk burden increases,” he noted. A normal aging eye, for example, shows some accumulation of senescent cells but, when a disease – macular degeneration or diabetes, for example – is also involved, senescent cells are even more abundant. Senescent cells express the protein p16. Ghosh said it is possible to engineer mice “so you can use a promoter to, essentially, tag the p16-positive cells and then inject a drug that will target those cells. In humans, you have to find a protein or target in the senescent cells that will kill those cells but not the neighboring, healthy cells.” Unity’s approach identifies these cells based on their state – specifically their expression of p16 and their secretion of inflammatory factors. The company’s lead asset, UBX1325, targets BCL-xl, which senescent cells - but not healthy cells – require for survival. “If you starve them of that, they are eliminated,” Ghosh explained. UBX1325 is being developed to treat diabetic macular edema (DME) and age-related macular degeneration. Upwards of 100 patients have been treated in early trials. UBX1325 pathology is injected into the eye, “so the entire eye is being bathed with this drug,” Ghosh said. As a result...disease is reduced, the anatomy looks good and the patients see better. The average gain was 7.5 letters or two lines on a vision chart. That gain was also seen in patients who had plateaued on anti-VEGF therapy and were treated with senolytics. A single injection appears to confer durable benefit. “We have patients who have been out to six months after a single injection and a very significant majority of them do not need a second injection. All gained vision well above where they started,” Ghosh said. The expectation is that senolytics may be able to bring the eye, in this case, to a younger state, prolonging its health span. Retinal imagery from Unity's Phase II DME study showing structural improvements/courtesy of Unity Biotechnology Senescent Cells Drive Disease Progression Bringing senolytic therapies to market will be aided by a growing acknowledgment of the root causes of aging. “Nephrologists have begun to realize that acute accumulation of senescent cells drives progression of disease and the pathologies associated with it and that this accumulation of inflammatory cells leads to more fibrosis and more inflammation,” Matthew Scholz, founder and CEO of Oisín Biotechnologies told BioSpace. “Senolytics is exciting because it’s the first of a class of therapy that has the potential to go after aging more broadly,” Scholz said. “Senescence seems to affect everyone and all the major organ systems in the body. One of the first things shown in transgenic animals was that if you remove (these cells) there was meaningful improvement in lifespan and healthspan. If we don’t recognize aging as a legitimate target for medical intervention, it will be difficult to move the needle,” beyond cosmetic treatments or lifestyle interventions. Beta-galactosidase, an enzyme in the lysosomes, was one of the early biomarkers for senescent cells. Images on Oisín’s website show no senescence in the kidney cells of 4-month-old mice, a considerable amount in the kidney tissue of 80-week-old mice and significantly less post-treatment. Studies show that mice treated with senolytics lived longer and had better health but, Scholz stressed, still eventually died. In mice, “Senolytics increased life span from birth by about 20%,” he recalled, “and if you’re counting (life extension) from old age, the improvement is massive. We’d lost half our control mice to old age before a single treated mouse died, so it’s really significant.” Oisín’s furthest-advanced senolytics program addresses kidney disease. “One application focuses on blocking the progression of acute kidney injury toward chronic kidney disease,” Scholz said. The other application is for people with advanced kidney disease who may be approaching renal failure. Eliminating the senescent cells probably won’t return those kidneys to full function, but it may retard or halt disease progression. The goal is to eliminate the p16 cells. The company does that by targeting p16+cells with a caspase-9 suicide gene. The senescent cells then die by apoptosis. Although the p16 pathway is critical in identifying senescent cells, it may not be the only possible pathway. As Scholz said, “the body has remarkable levels of redundancy. For most systems, there’s more than one pathway.” Recognizing that, the company’s new frailty study targets both the p16 and p53 pathways, creating a synergistic, two-pronged method of killing senescent cells. That approach may be applied to its kidney program in the future. The question of unintended consequences is ever-present when pioneering new fields. Oisín attempted to address that in a blinded comparison study of non-human primates who received either placebo or the therapy. There were no discernable differences, according to the pathologist, Scholz said. “It’s an admittedly low-tech method, but the treatment didn’t appear to cause any harm.” Senolytics is a completely new type of therapy that, at this admittedly early stage, appears to have great promise. If it delivers on that promise, it will change what it means to age irrevocably.