Researchers redefine cell death in disease and drug discovery.
Life cannot exist without death, whether we’re discussing ecosystems, individual species, or single individuals. At each level, there is a churn of the old and defective to make way for the new and vigorous.
With that in mind, there is a growing understanding of the roles that cell death pathways play in keeping a body healthy, and equally, the hazards of those pathways running amok in human disease. And whereas death may be feared at a macro level, researchers are plumbing its depths for ways to combat diseases, from oncology to autoimmunity and injury to inflammation.
1000 ways to die
Of the various cell death pathways that researchers explore, the best understood is apoptosis, long held to be the only regulated form of cell death. Apoptosis is largely a protease-mediated process where enzymes called caspases cleave intracellular proteins, leading to mitochondrial and membrane disruption, as well as breakdown of genomic DNA into nucleosomal fragments.
In health, apoptotic pathways are an essential component of embryological development and throughout life to facilitate cellular turnover and tissue regeneration. It is also a tool of the immune system to combat infection and eliminate damaged tissues.
Although researchers had first described cell death processes decades earlier, they didn’t really begin to explore the morphological changes that apoptosis triggered in cells until the 1970s. By the 1980s and 1990s, researchers dissected the genetics of apoptosis, offering therapeutic targets.
“When I was getting into research in the late 90s, apoptosis was absolutely the hottest thing in cell biology,” Scott Dixon, a cell biologist at Stanford University, recounted. “That was such a powerful paradigm that it overshadowed, for quite some time, a whole series of observations that maybe cells were dying in a way that was regulated but was not apoptosis.”
He recalled that Peter Vandenabeele, now at the VIB-Ugent Center for Inflammation Research, studied the influence of tumor necrosis factor-α (TNF-α) on cell death in the 1990s. In those studies, researchers tried to block cell death using caspase inhibitors, but instead exacerbated cell death.
“It took some time to understand what that was, but ultimately Junying Yuan at Harvard figured out that this was necroptosis,” Dixon said, adding that Yuan’s 2005 paper in Nature Chemical Biology was the catalyst for the notion that non-apoptotic cell death could be regulated (1).
When I was getting into research in the late 90s, apoptosis was absolutely the hottest thing in cell biology,
- Scott Dixon, Stanford University
Whereas researchers initially noted apoptosis from its morphological effects, Yuan’s 2005 study identified necroptosis through small molecule screening experiments that led to the discovery of a molecule they dubbed necrostatin-1. The researchers also found that necrostatin-1 inhibits the activity of RIPK1, an enzyme that modulates TNF signalling.
Rather than trigger proteolysis, necroptosis compromises the integrity of the cell membrane, facilitating the release of cytokines and a cocktail of molecules known as damage- and pathogen-associated molecular patterns (DAMPs, PAMPs). In response to this release, immune cells move to the area of injury or infection to initiate healing.
Beyond infection, Yuan and colleagues have explored the role of RIPK1 and necroptosis in acute disorders, such as ischemic and traumatic brain injury, and neurodegenerative conditions, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and multiple sclerosis (2).
Dixon’s approach to research followed a similar trajectory to Yuan’s. His postdoctoral work in the lab of Brent Stockwell at Columbia University on small molecule screening in cancer cells suggested the possibility of yet another cell death mechanism beyond apoptosis. Because this process involved iron and oxidative species, the researchers named it ferroptosis, which Dixon described as more of a chemical process versus the proteolysis of apoptosis.
“Membrane lipids in the cell become oxidized, and in some way that is poorly understood, that membrane lipid oxidation ultimately leads to fragmentation of the membrane and death of the cell,” he explained.
Using chemical screens, researchers identified radical-trapping antioxidants such as liproxstatin-1 and ferrostatin-1, as well as inhibitors of glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11, which help reduce the lipid hyperoxides, the mediators of ferroptosis (3).
Yet another cell death pathway, pyroptosis, acts in response to microbial infection. Cells recognize DAMPs and PAMPs to activate inflammasomes and proinflammatory cytokines such as IL-1β and IL-18. The inflammasomes activate caspase-1, which cleaves intracellular proteins, creating fragments that form pores in the cell membrane, triggering cell rupture. Inflammasomes also oligomerize proteins that can accumulate in the brain and seed amyloid-β and tau protein deposition, leading to neuroinflammation (4).
As researchers proved with apoptosis, this tetrad of cell death pathways — apoptosis, necroptosis, ferroptosis, and pyroptosis — may not represent the only pathways. Dixon gave the example of entosis, where one cell completely encapsulates another. Michael Overholtzer from the Memorial Sloan Kettering Cancer Center first noted the phenomenon in cultured cancer cells, but according to Dixon, Overholtzer has since found evidence of entosis in tissue sections in research papers as far back as the 1950s.
Despite his personal enthusiasm for the possibilities, Dixon recognized the caution from many of his colleagues in the cell death community.“Are you going to really call every type of stress that yields a death that isn't exactly fitting with a known mechanism, a new -optosis?” he asked. “That seems extreme, and it could lead to a situation where you have hundreds of different names out there, which then becomes a little bit meaningless.”
As scientists describe more potential cell death pathways, it will be vitally important to show their physiological relevance. “You can take a car, pull out dozens of different parts, and the car won't run for any number of reasons,” Dixon suggested. “But what does that tell you about how a car works? The car only works in one way.”
“Same thing in a cell,” he continued. “You can probably take out dozens of genes or proteins and kill it in some way, but are those mechanisms used physiologically? That part is unclear, and I think that's where people want to see the evidence.”
Clinical relevance is an easy sell with apoptosis, Dixon acknowledged, because researchers first described the phenomenon in clinical samples such as tissue sections from patients and disease models. Researchers investigated the molecular mechanisms of cell death in those cells.
Necroptosis and ferroptosis have been a harder sell, he added, because researchers started with an interesting phenotypic impact in cells in a dish, and then had to link those effects to human physiology. Researchers are slowly making those links, and companies have started to explore drug development targeting these other cell death pathways.
To fill those pipelines, however, researchers first need to explore the multiple pathways by which cell death occurs and the potential interplay of those pathways to identify possible drug targets. That effort requires new assays and instruments.
Just as researchers add to the list of cell death pathways, they are also developing more tools to tease apart cell death mechanisms and pathways. To get as much information as possible, scientists need tools that can test as many aspects of cell death as possible. As Dixon argued, if you look for something specific, you will either find it or not, but you may miss other interesting effects.
To start, researchers have looked to readouts of apoptosis to understand cell death. For example, researchers can use a fluorescence resonance energy transfer (FRET) reporter to study caspase cleavage, or they can monitor the translocation of cytochrome C from mitochondria into the cytosol.
“Nothing wrong with that when you're studying apoptosis,” Dixon said. “As long as you understand that that will only tell you about apoptosis, that's great.”
Appreciating the potential for many different forms of cell death, however, Dixon wanted a method that would allow him to examine death in an unbiased way. He didn’t want an assay tied to one specific biochemical pathway.
He also felt that because cell death was a dynamic process, it was critical to record the process over time so that he could understand when and how cells were dying and differentiate the impacts of different test compounds. He decided to build from the traditional dye- and fluorophore-based rapid assays for cell viability and cell death, whether broadly or specific to apoptosis.
In a 2017 paper published in Cell Systems, Dixon and his colleagues introduced a high-throughput screening method called scalable time-lapse analysis of cell death kinetics (STACK), which combined living (mKate2) and dead (SYTOX green; SG) cell markers with time-lapse imaging and mathematical modeling to quantify the kinetics of compound-induced cell death (5).
After adding test compounds to the multiwell dish housing their cell cultures, the researchers monitored the number of cells labeled with mKate2 and SG using an automated high-throughput microscope, imaging every two hours for up to 118 hours. By repeating this process, the researchers evaluated the effects of more than 1800 bioactive compounds on cell death in two human cancer cell lines.
Using mathematical modeling, the researchers determined two key parameters of cell death kinetics: the time between addition of the test compound and onset of cell death within the population (DO) and the maximal rate of cell death within the population (DR).
They found that while several dozen compounds induced cell death in both cell lines, the DO and DR of some compounds varied. Furthermore, they noted that compounds exhibiting similar overall maximal lethality showed significant variation in DO and DR, meaning that experiments relying on a single timepoint offer a limited understanding of how a compound kills cells.
For example, two compounds may kill the same number of cells after one day, but one compound may start killing shortly after addition to the cells (low DO), but take a long time to kill all the cells (low DR), whereas the other compound may take a while to start killing cells (high DO), but do so rapidly once it has started (high DR).
Through various experiments, the researchers began to understand the cell death synergies and conflicts between compounds, how cell culture conditions influenced cell death kinetics, and how the mechanisms of cell death differed between molecules.
“We suspected these phenomena existed, but without the technology to measure them, we weren't certain,” Dixon noted. “This has really opened our eyes to these differences in kinetics. We think that they are important to understand.”
More recently, Dixon and his colleagues performed a similar STACK experiment that identified several dozen ferroptosis suppressors, including many that worked via off-target antioxidant or iron-chelating processes (6). One such compound was bazedoxifene, which is approved by the FDA to treat postmenopausal osteoporosis. It acts as a potent radical-trapping antioxidant.
Dixon and colleagues performed their STACK experiments with 2D cell cultures, which does not reflect the typical 3D environment in which cells organize as tissues or tumors. It is well known that cells on a plate do not completely recapitulate the characteristics of cells in native tissue.
To address this challenge, Ghent University’s Dmitri Kyrsko and his colleagues developed a cell death analysis method called 3D cell death assay (3DELTA) to study and monitor ferroptosis in tumor spheroids, an environment closer to a tumor’s natural microenvironment (7).
The researchers used SYTOX Green and Blue as indicators of cell death, establishing the experimental upper limit by permeabilizing the cells with Triton-X, which would simulate 100% death. They then treated the cultures with an apoptosis inhibitor, necroptosis inhibitor, and three different ferroptosis inhibitors before inducing cell death with the GPX4 inhibitor ML-162.
The researchers noted that only those spheroids treated with ferroptosis inhibitors demonstrated reduced cell death, confirming that ML-162 was a ferroptosis inhibitor. They also noted that the apoptosis inhibitor seemed to increase cell death, suggesting that the drug might have induced necroptosis by inhibiting caspase-8.
The researchers found that ML-162 induced cell death in approximately 90% of cells in 2D culture. That rate was only 30% (Day 10 cultures) to 50% (Day 1) in 3D culture, indicating the significant role cellular environment has on cell death kinetics.
The researchers suggested that running the 3DELTA experiments in an incubator would enable longitudinal experiments, offering real-time kinetic and high-throughput measurements. And because the researchers don’t have to disaggregate the spheroids to get experimental read-outs, 3DELTA retains the tumor-like structure and is likely to provide physiologically relevant data.
As much as these methods will help to identify new cell death pathways, serve to improve the understanding of known pathways, or even generate preclinical leads, companies are actively taking what they already know to fill their pipelines with modulators of cell death pathways.
Delivering cell death
Given the desire to stop uncontrolled cell proliferation, the most active area of clinical exploration for drugs modulating cell death pathways is in cancer.
Ascentage Pharma, for example, has several apoptosis-inducing programs targeting a variety of solid and haematological malignancies.
At the American Society for Clinical Oncology Annual Meeting in June, company researchers presented findings from their first-in-human clinical trial of APG-2575 (Lisaftoclax) in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/ALL) and other liquid tumors. APG-2575 inhibits the activity of B-cell lymphoma-2 (BCL-2), a protein that inhibits tumor cell apoptosis when overexpressed, a phenomenon that can occur in these types of cancer.
The researchers noted that treatment with APG-2572 offered a favorable safety profile and an overall response rate of 80% in patients with R/R CLL/ALL. Of the 21 patients with R/R non-CLL/ALL, half achieved at least stable disease.
Even as the company presses forward with clinical development of APG-2575 (it currently has 10 active or recently completed clinical trials), Ascentage Pharma continues to explore synergies for the BCL-2 inhibitor. Last year, for example, Sun Yat-Sen University Cancer Center’s Jian Sun and colleagues tested the antitumor activity of APG-2575 in combination with other cancer therapeutics: the BTK inhibitor, ibrutinib, or Ascentage Pharma’s MDM2-p53 inhibitor, APG-115, in R/R diffuse large B-cell lymphoma (DLBCL) tissues and xenograft mice (8).
The researchers showed that APG-2575 alone induced tumor cell apoptosis in DLBCL cell lines with increased BCL-2 expression, an effect that was also observed in mice with subcutaneous xenografts. The researchers then evaluated APG-2575 and ibrutinib together, hoping to enhance the BTK inhibitor’s limited efficacy and diminish the risk of drug resistance. They found that APG-2575 increased the inhibitory effect of ibrutinib on DLBCL cells, increasing apoptosis to levels not seen with either drug alone, and they found that the drug combination also enhanced suppression of tumor growth in vivo.
The results were largely similar for the combination of APG-2575 and APG-115, and they noted that the combination reduced the expression of anti-apoptotic proteins while upregulating the expression of apoptotic effector BAK.
Also targeting BCL-2, AstraZeneca researchers developed a dual BCL-2/BCL-xL inhibitor called AZD4320 that is designed to trigger apoptosis in tumor cells. Unfortunately, the scientists noticed dose-limiting cardiovascular toxicity in AZD4320 that prevented them from moving to the clinic (9).
Earlier this year, however, Marianne Ashford and her colleagues at AstraZeneca described their efforts to develop a dendrimer-conjugate version of AZD4320 that could retain its efficacy while minimizing its toxicity. They used mathematical modeling to identify an optimal release rate using different linkers, looking for a balance between greater activity with faster-releasing linkers and reduced toxicity with slower-releasing linkers.
After several rounds of modeling and synthesis, the researchers settled on AZD0466, which exhibited potent and dose-dependent anti-tumor efficacy resulting from activation of the mitochondrial apoptosis pathway. Furthermore, they noted that the new design improved cardiovascular tolerability without losing efficacy.
Testing AZD0466 against a disseminated DLBCL model, the researchers found decreased tumor burden in multiple locations. They also noted enhanced efficacy when they combined the dendrimer-conjugated compound with standard of care chemotherapy, rituximab and acalabrutinib, showing AZD0466 could be safely and effectively combined with other therapies.
The company recently initiated Phase 1 clinical trials of AZD0466 monotherapy in advanced solid and haematological tumors.
Much more nascent in development are treatments targeting the ferroptotic pathway, where much of the research remains in academic centers. That is beginning to change, however, as ferroptosis specialists launch or support new companies.
In June, for example, Harvard University’s Stuart Schreiber and colleagues launched Kojin Therapeutics with a focus on ferroptosis. Their goal is to target disease-associated cells, starting with ferroptosis-sensitive cells in particular, wherever they might be, rather than focusing on a particular cell type or tissue.
Similarly, BridgeBio Pharma affiliate Ferro Therapeutics develops covalent inhibitors of GPX4, the enzyme that neutralizes free radicals at the lipid membrane, protecting cells from ferroptosis. In preclinical studies, their lead compound BBP-454 demonstrated activity as a monotherapy and reduced tumor volume in a mouse xenograft model of renal cell carcinoma.
“[GPX4] emerged early on in the basic studies of ferroptosis from Brent Stockwell's lab as a candidate target,” explained Dixon, who is an adviser to Ferro. “Ferro’s goal is to go after the ferroptosis pathway for cancer treatment.”
“Nothing has been publicly disclosed to my knowledge about exactly the strategies that are being pursued there,” he added. “But that certainly is another indication that there's commercial interest in this area.”
Taking GPX4 out of the cancer domain, Jean Bopassa and colleagues at the University of Texas at San Antonio evaluated the ability of liproxstatin-1 (Lip-1) to disrupt ferroptosis induced during ischemic/reperfusion (I/R) injury in mice (10). The researchers found that Lip-1 offered cardioprotective effects when administered at the start of reperfusion.
They noted that Lip-1 significantly reduced the size of myocardial infarct, and using electron microscopy, they found that treatment resulted in protection of mitochondrial structural integrity as well as preserving the cardiac contraction machinery. At the molecular level, the researchers found that Lip-1 reduced the levels of anion channel VDAC1 and restored the levels of GPX4 otherwise diminished by I/R-related stress.
Meanwhile, targeting necroptosis pathways, researchers at GSK conducted a Phase 1 clinical trial of RIPK1 inhibitor GSK2982772 in patients with active plaque psoriasis, knowing that RIPK1 inhibitors prevent TNF-mediated inflammation in multiple preclinical models (11). The researchers found that at least one dose improved multiple disease progression endpoints as well as quality of life indices. Histologically, they also noted that the therapy reduced epidermal thickness as well as T cell infiltration into both the dermis and epidermis.
Separately, Huazhong University of Science and Technology’s Hongxiang Chen and colleagues evaluated RIPK1 inhibitor necrostatin-1 derivative Nec-1s and an inhibitor of downstream partner MLKL, necrosulfonamide (NSA), both in vitro and in a mouse model of psoriasis (12).
The researchers induced necroptosis in keratinocytes and then treated the culture with Nec-1s or vehicle. They found that Nec-1s not only inhibited necroptosis, but also stimulated cell viability. The treatment downregulated expression of the necroptotic proteins RIPK1, RIPK3, and MLKL as well as inflammatory cytokines. The researchers found that pre-treatment of mice with Nec-1s before induction of psoriasis dermatitis significantly attenuated the clinical and histological hallmarks of skin inflammation.
The team further found that treatment with NSA was even more effective than treatment with Nec-1s, both in terms of clinical phenotype and histological changes. They found that NSA, but not Nec-1s, could reduce the level of DAMPs, suggesting that MLKL may play a role in RIPK1-independent cell death pathways.
This data showed that keratinocyte necroptosis was a key component of psoriatic inflammation, but the causal relationship between the two yet remained a “chicken-and-egg” situation, said the study authors. Along with their work, Chen and colleagues see the GSK research as a step in the right direction.
Although apoptosis remains the primary focus of most drug development pipelines involving cell death pathways, progress is being made to explore the other pathways by leveraging some of the same experimental insights and methodologies.
The need to kill rapidly proliferating cells may be obvious, but sometimes that’s not what happens. Instead, some cells shut down their cell cycle and exist in an undead, zombie-like state called senescence. Such is the focus of the work at Oisin Biotechnologies.
Matthew Scholz, CEO of Oisin Biotechnologies, explained that while cancerous mutations can metaphorically cause cells to push their gas pedals to the floor, dividing rapidly and conquering via metastases, the mutations that create senescent cells act quite differently. Like cancer cells, senescent cells are resistant to death, but they are rarely immortal.
Even though they have stopped dividing, senescent cells are still metabolically active. Their contribution to conditions like cardiovascular disease, chronic kidney disease and aging is in large part due to the secretion of pro-inflammatory cytokines, chemokines, growth factors, and metalloproteinases, a process called the senescence-associated secretory phenotype (SASP). This pathway can trigger damage in surrounding tissues.
Efforts to address the senescent phenotype have largely taken one of two directions: senomorphics, which attempts to return cells to a more natural state, and senolytics, which seeks to destroy senescent cells.
Oisin Biotechnologies is firmly in the latter camp, in part, Scholz explained, because cancer and senescent cells are not completely dissimilar.
Many, if not all, of the typical senescent cell promoters are also tumor suppressor promoters. So, from Scholz’s perspective, senescent cells may only be one or two mutations away from reactivating cell division and becoming cancerous. This is why he struggles with the philosophy behind senomorphics.
“The last thing you want to do is re-enter the cell cycle,” he said. “The cell has stopped its own division for good reasons and trying to override that, I think, is rather foolhardy.”
Oisin Biotechnologies’ approach centers on its SENSOlytics platform, which combines a proteolipid delivery vehicle with apoptosis-promoting in-vivo gene therapy.
The company developed the proteolipid particle, Scholz explained, to overcome two key limitations of more traditional lipid nanoparticles, which he described as a Faustian bargain. If the nanoparticles were neutrally charged, they are very tolerable, but struggle to enter cells. If they are charged, however, they can enter cells but struggle with toxicity issues.
To deal with these issues, Oisin Biotechnologies relies on a fusion-associated small transmembrane (FAST) protein that scientists discovered facilitates infection in reoviruses. Compared with something like the influenza fusion protein or SARS-CoV-2 spike protein, Scholz explained, the fusogenic FAST proteins are miniscule, a factor that is particularly useful for the SENSOlytics platform.
“The ectodomain of [the FAST protein] is only about 12 amino acids long, so it’s basically invisible to the immune system,” he commented.
The FAST protein allows the company’s proteolipid particle to be neutrally charged, facilitating cell entry and reduced toxicity. It can bind to any cell in the body, increasing the likelihood of treatment reaching any senescent cell, regardless of tissue origin.
Keeping the medicinal effect to senescent cells and not healthy tissues is where the gene therapy design comes into play. Scholz’s previous experience with a company called Immusoft involved genetically altering plasma cells to secrete proteins offering therapeutic benefit. At Oisin Biotechnologies, he extended that approach.
“What if, instead of programming [cells] to produce something, you wrote logic gates in DNA that said: if something, then something?” he said. “In this case, if you’re damaged, kill yourself. If you’re cancerous, kill yourself.”
Researchers at Oisin Biotechnologies took advantage of the significant upregulation of the signalling molecule p16 when a cell becomes senescent by engineering the p16 promoter to control expression of the pro-apoptotic caspase-9 gene. Thus, when the gene therapy enters a senescent cell, the transcription factors involved in p16 expression also turn on caspase expression, killing the cells.
Using the construct, company researchers have seen as much as an 80% reduction in senescent cells in culture and a reduced senescent cell burden in naturally aged mice.
The company has a similar program running at its spin-off OncoSenX, formed with partner Entos Pharmaceuticals. Entos Pharmaceuticals developed the Fusogenix delivery system for Oisin Biotechnologies’ gene therapy. OncoSenX tackles cancer using the promoter of the p53 signalling molecule.
“It's hard to be cancerous if p53 works because the first thing you'll do is arrest cell division,” explained Scholz, who is also the cofounder and CEO of OncoSenX. “So, cancers mutate p53 or delete it.”
When that occurs, the cell tries to rescue p53 function by upregulating the transcriptional pathway for p53 by orders of magnitude.
“So, if you administer a little genetic program with a synthetic, engineered p53 promoter, all those transcription factors glom onto it, and it makes whatever we told it to,” Scholz added. In this case, they told it to make caspase-9.
He also noted that unlike a lot of cancer treatments that can drive mutation in tumor cells, the OncoSenX approach shouldn’t. “A cell is either killed within one cell cycle or not at all,” Scholz explained. “The caspases are very fast.” And because caspases are not toxic in and of themselves, they shouldn’t exert pressure on the surrounding tissues.
Chronic kidney disease (CKD) is the most advanced program at Oisin Biotechnologies, although it is still in the preclinical phase of development. Working with Joe Bonventre and colleagues at Brigham and Women’s Hospital, company scientists have shown that although senescent cells are a natural part of wound healing, SASP behavior triggers a positive inflammatory feedback loop that continues all the way to end-stage renal failure. Thus, Scholz explained, senescent cells drive disease progression.
To date, company researchers have succeeded in eliminating senescent cells in mouse models of CKD, but Scholz acknowledged that the translation to clinical efficacy can be a major hurdle, pointing to the setback experienced by Unity Biotechnology in 2020.
Unity Biotechnology’s UBX0101 was the first senolytic treatment to reach clinical trials. The company developed the small molecule inhibitor of the interaction between MDM2 and p53 to treat moderate-to-severe painful osteoarthritis (OA) of the knee.
Although researchers saw improvement in mouse models of OA, Phase 2 studies of the drug failed to show any significant improvement in joint pain or stiffness from baseline compared to placebo. Scholz looked back to a preclinical study in mice published in Nature Medicine to explain the clinical challenges (13).
He noted that because the research team, led by Johns Hopkins University’s Jennifer Ellisseeff, administered UBX0101 by intra-articular injection, they were likely only treating local senescent cells, leaving other senescent cells in the body to contribute to the OA. He suggested that this might be why treatment worked better in young mice than in older mice, which would have a higher systemic senescence burden.
The authors of the study reported that although UBX0101 cleared senescent cells from aged articular cartilage, age-related decline in the proliferative and synthetic capacities of articular chondrocytes might impair tissue regeneration. They further suggested that additional treatments or even systemic treatment might be required in older animals to reduce disease burden and regenerate cartilage tissue.
Although Unity Biotechnology terminated the UBX0101 program following the Phase 2 results, the company continues to pursue other senolytics programs, including its BCL-xL inhibitor, UBX1325.
In July, researchers at Unity Biotechnology reported positive efficacy and tolerability data from a Phase 1 clinical study of UBX1325 in patients with advanced ophthalmic disease due to diabetic macular edema (DME) and wet age-related macular degeneration (wet AMD) refractory to anti-VEGF therapy. Specifically, patients receiving a single injection of UBX1325 saw improvements in clinical measures of disease progression, such as best-corrected visual acuity and central subfield thickness.
Senescence and cell death may share yet another common characteristic; these processes are still somewhat mysterious.
“I don't think all the populations of senescent cells are known to science today,” Scholz suggested. “I think we'll continue to find more in interesting pathways.”
If you ablate all these cells in mice, he continued, the mice live longer, but they're not immortal. Senescence is not the only thing that goes wrong.
“We look at it as being the pointy end of the spear,” he said. And just like so many of the cell death mechanisms, that spear is likely to puncture some cells before the day is done.
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- Duan, X. et al. Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation. Cell Death Dis. 11, 134 (2020).
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