University of Central Florida

ORLANDO, Fla.--( BUSINESS WIRE )--Researchers from Hesperos and the University of Central Florida have developed a groundbreaking model using human induced pluripotent stem cell (iPSC)-derived cortical neurons to better understand and combat Alzheimer’s disease (AD). Their study, “ A functional aged human iPSC-cortical neuron model recapitulates Alzheimer’s disease, senescence, and the response to therapeutics ," has been published in the prestigious journal Alzheimer's & Dementia ® : The Journal of the Alzheimer's Association. doi.org/10.1002/alz.14044 AD affects an estimated 6.2 million Americans aged 65 and older, with projections suggesting this number could reach 14 million by 2050. Current treatments, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only temporary relief. The high failure rate of AD clinical trials highlights the need for a better understanding of the pathophysiology and drug mechanisms. The study addresses a critical challenge in Alzheimer’s research: the degeneration of cortical layers associated with cognitive decline. Despite substantial efforts to date, few current AD therapies are not disease-modifying. The team accurately reproduced key biological aspects of aging and senescence in a multi-cellular microphysiological system (MPS), also known as a Human-on-a-Chip. This new approach reveals how cellular aging, also known as senescence, contributes to disease progression and therapy resistance, providing researchers with an accurate, human platform to further understand the disease and potential therapeutics in a living context. Further, since other platforms at Hesperos, based on neurodegenerative diseases, have been accepted by the Food and Drug Administration (FDA) for efficacy data, it provides a new method to accelerate development and regulatory submissions of new treatments. This model provides an invaluable tool for real-time measurement of neuronal activity and aging biomarkers, facilitating drug screening and the development of AD therapies. It also reveals complex disease mechanisms, such as the role of inflammatory factors in neuronal senescence and how it differs from non-disease age-related controls, offering new targets for intervention. Researchers cultured human iPSC-derived cortical neurons on patterned microelectrode arrays to measure long-term potentiation (LTP) noninvasively. LTP, a quantifiable metric for learning and memory, is directly impacted by central nervous system neurodegeneration. By treating these neurons with pathogenic amyloid-β (Aβ), a peptide that plays a central role in development of AD, to mimic disease pathophysiology, the team was able to analyze senescence and therapeutic responses. The study demonstrates that this novel human iPSC-cortical neuron model of aging, cultured in serum-free, defined conditions, accurately recapitulates hallmarks of AD showing the following: Pathological Insights : Aβ42 induced synaptic damage, accelerated neuronal senescence, impaired mitochondrial potential, and increased reactive oxygen species (ROS), leading to oxidative stress and inflammation. Therapeutic Responses : Drugs such as memantine, rolipram, saracatinib, and donepezil improved neuronal function and viability, though they did not completely halt Aβ42-driven senescence. The study underscores the potential of biomimetic MPS systems in translational research. By integrating clinically relevant neuronal function with proteome responses, this platform is poised to accelerate the discovery of novel neuroprotective compounds for AD and other neurological disorders. “This marks a significant step forward in Alzheimer's research by providing a deeper understanding of AD pathophysiology in a human aged MPS platform. We are excited about the potential of this model to transform drug discovery in AD, providing hope for patients,” said J. Hickman, PhD, co-founder and Chief Scientist of Hesperos and Professor of Chemistry at UCF. This research was supported by grants from the National Institutes of Health (R44TR001326, R44AG058330). Research Article : doi.org/10.1002/alz.14044 Nanoscience Technology Center (NSTC) at the University of Central Florida (UCF) The mission of the NSTC is to establish a cutting-edge research program in materials and nanotechnology, provide high quality training for students and facilitate the advance of innovations to solve real world technology challenges. https://nanoscience.ucf.edu/ Hesperos, Inc. Hesperos is a global contract research organization (CRO) providing drug development services using its Human-on-a-Chip ® platform - the most advanced, multi-organ microphysiological systems available today. https://hesperosinc.com

Pictured: NK cells attacking a cancer cell/ selvanegra for iStock When the first CAR T cell therapy was approved by the FDA in 2017, it was heralded as a breakthrough in cancer treatment. The approach allowed for a targeted attack on cancer cells using a patient’s own immune cells, as compared with the broad-strokes assault levied by traditional treatments such as chemotherapy and radiation. While a total of six CAR-Ts have been approved to date, the approach works only for a subset of patients, has shown promise mainly for blood cancers and has notable side effects. To overcome these shortcomings, many researchers and biotech companies have turned their attention to natural killer (NK) cells, which are a part of the innate immune response—the body’s first line of defense against any infection. Historically, NK cells have been notoriously difficult to culture, leading them to be overlooked, said Alicja Copik, associate professor of medicine and core scientist at the University of Central Florida. “Better understanding of how to grow [NK cells] in the laboratory has led to an immense research interest in these cells,” she told BioSpace. “A decade ago, just one company was looking at NK cells. Now, several groups are exploring different ways to use them as cell therapies.” Overcoming CAR-T’s Challenges CAR-T therapies involve reengineering T cells, typically derived from the patient. Once isolated, these cells are genetically modified to express chimeric antigen receptors (CARs) on their surface, arming them to better recognize and attack cancer cells. However, CAR-Ts have been shown to cause several side effects, including cytokine release syndrome, neurotoxicity and blood disorders such as anemia and thrombocytopenia. In terms of allogeneic CAR-Ts, where donor T cells are used, there is the risk of graft-versus-host disease, a strong immune reaction that leads to a rejection of the transplanted cells. “T cells with CARs can go crazy and grow uncontrollably, which leads to some of the major side effects,” said Sumiti Jain, chief scientific officer of ImmuneBridge, a San Francisco–based biotech startup that raised $12 million in seed funding in 2023 to develop NK cells from the umbilical cord. NK cell–based therapies do not cause cytokine release syndrome and neurotoxicity because “they don’t grow as robustly,” Jain said. CAR-Ts have also been associated with secondary malignancies such as leukemias, skin cancers and T cell non-Hodgkin lymphomas. Noting this potential side effect, the FDA recently announced that it will require an update to the boxed warnings of CAR T cell therapies, alerting patients and prescribers to a heightened risk of secondary T cell malignancies. Furthermore, David Shook, chief medical officer of Nkarta, which is developing allogeneic CAR-NK cells, told BioSpace that CAR T cell therapies, despite their benefits, have remained largely inaccessible to patients due partly to a “cumbersome” manufacturing process. The process of isolating and engineering a patient’s T cells takes over two weeks before the cells can be infused back into the patient. “There are patients who are eligible for CAR-Ts and are on the waitlist but are not able to access them because of manufacturing constraints,” Shook said. Advantages of NK Cell Therapy Ann Cheung, chief scientific officer and head of R&D at Dragonfly Therapeutics, which is developing NK cell–stimulating antibodies, noted that, unlike CAR-T therapies, NK cell therapies do not require patients to undergo lymphodepletion chemotherapy with toxic agents such as fludarabine and cyclophosphamide. “Not every patient is eligible for these chemotherapies,” she told BioSpace, because of other immune conditions or a susceptibility to infections. “In that sense, the safety pro NK cell therapies is much better.” Moreover, she said, NK cells work by recognizing multiple antigens, making them strong contenders to destroy cancer cells. NK cell therapies have also shown promise for treating solid cancers, an area where CAR-Ts have largely failed to show benefits, Jain said. “CAR-Ts are amazing for blood cancers, but put them in solid tumors, and they seem to freeze.” NK cells seem to have the ability to migrate into solid tumors better than CAR-Ts, she explained. These characteristics have inspired several biotech and research groups to explore the potential of turning NK cells into therapies. Nkarta is developing CAR-NK cells from a donor-derived pool of NK cells. But after seeing initial success with one candidate, NKX101, an interim evaluation of Phase I data in 14 acute myeloid leukemia patients showed a “meaningfully lower” response rate than in the first six reported patients, causing the company to deprioritize the program. Other companies are moving forward with CAR NK cell therapy candidates. Fate is in Phase I trials with FT522 for B cell lymphoma, and Century has a CD19-targeting therapy, CNTY-101, in Phase I for B cell malignancies. And while some are focused on genetically modifying NK cells to enhance their cancer-fighting abilities, others are harnessing the inherent qualities of NK cells. For example, San Diego–based Artiva Biotherapeutics, in partnership with Merck, is developing a non–genetically modified NK cell therapy that enhances antibody responses to specific cancers and autoimmune diseases. Meanwhile, NKGen Biotech just released interim Phase I data for its allogeneic non–genetically modified NK cell therapy, SNK02, showing that it was well tolerated—all patients completed the eight treatment cycles—and showed signs of clinical activity against pretreated solid tumors. And ImmuneBridge wants to harness the pool of NK cells from hematopoietic stem cells derived from umbilical cords, which Jain said are most likely to show anti-tumor activities against specific cancers. The Road Ahead Despite recent advancements, experts suggest the road ahead for upscaling NK cell therapies may not be straightforward. “NK cells don’t live for very long,” Shook said, so patients may require a high dose and multiple rounds of injections. Jain added that differentiating NK cells derived from donors can exhaust the cells and mellow their potential to be effective cancer killers. “We need durable cell NK therapies,” she said. According to a study of clinical trial data recently published in Nature, the clinical benefits from NK cell–based therapies often lasted only a few months before relapse, likely due to resistance or low NK cell persistence. “NK cell persistence typically ranges from a few days to 4 months, with an average of 7 days,” the authors noted, adding that cryopreservation of NK cells further impacts their ability to grow. While there are currently no FDA-approved NK cell therapies for cancer, Copik is hopeful that some of these therapies will make it to market. “More studies are showing us that the NK cell therapies are effective and have better safety profiles compared to CAR-Ts,” she said. Jain holds a similar view. “Patients are battling every day. Having a new therapy that is readily accessible will be a huge advancement.” Aayushi Pratap is a New York-based health and science journalist and an alum of Columbia Journalism School. Reach her on LinkedIn.

Researchers are on a mission to kill drug-resistant bacteria, and a new study has identified a therapy that can penetrate the slime that such infections use to protect themselves from antibiotics.Researchers have shown that an antimicrobial peptide from cows has potential for treating incurable infections from the bacterium Klebsiella pneumoniae. The bacteria, commonly found in the intestines, is usually harmless. It becomes a health hazard when it enters other parts of the body and can cause pneumonia, urinary tract and wound infections. Those at highest risk include seniors and patients with other health problems such as diabetes, cancer, kidney failure and liver disease. University of Central Florida College of Medicine researcher Renee Fleeman is on a mission to kill drug-resistant bacteria, and her latest study has identified a therapy that can penetrate the slime that such infections use to protect themselves from antibiotics. In a study published recently in Cell Reports Physical Science, Fleeman showed that an antimicrobial peptide from cows has potential for treating incurable infections from the bacterium Klebsiella pneumoniae. The bacteria, commonly found in the intestines, is usually harmless. It becomes a health hazard when it enters other parts of the body and can cause pneumonia, urinary tract and wound infections. Those at highest risk include seniors and patients with other health problems such as diabetes, cancer, kidney failure and liver disease. However, younger adults and people without additional health problems can acquire urinary tract and wound infections from the bacteria that cannot be treated by antibiotics available today. The CDC reports that antibiotic resistant bacteria are a growing global health threat. A 2019 study found that nearly 5 million people died worldwide that year from drug-resistant infections. A large portion of those deaths are attributable to K. pneumoniae because it has a 50% death rate without antibiotic therapy. These bacteria are more resistant to drugs when they live in a biofilm -- microorganisms that stick together and are embedded in a protective slime. Recent studies have shown that 60-80% of infections are associated with bacteria biofilms, which increase their drug resistance. "It's Iike a coat that bacteria put around itself," Fleeman says. Her research is examining ways to remove the protective coat and expose the bacteria so it can be killed by the body's immune system or antibiotics that currently cannot pass through the biofilm. Through that research, Fleeman discovered how the peptides made by cows can quickly kill K. pneumoniae. She determined that the peptides interact with sugar connections that keep the slime intact. She likened the process to cutting into a chain-linked fence. Once multiple chains are cut, the integrity of the slime structure is damaged, and the peptide can enter and destroy the bacteria that are no longer protected. "Our research has shown polyproline peptide can penetrate and begin to break the slime barrier down in as little as an hour after treatment," says Fleeman. The peptide has another advantage -- once it breaks through the protective slime barrier, tests showed it killed the bacteria better than antibiotics used as a last resort to treat incurable infections. Peptides kill the bacteria by punching holes in their cell membrane, causing death quickly compared to other antibiotics that inhibit growth from inside the cell. The peptide could also be used as a topical treatment for a wide range of uses, especially for the military, to treat open wounds in the field. "Bacteria divide every 30 minutes, so you have to act fast," Fleeman says. The next phase of her research will seek to understand the biology behind the peptide's efficacy and if combinations of other drugs would aid in its application. Her research is funded through a three-year National Institutes of Health funding Pathway to Independence R00 grant and is in its second year. Her study initially started as a K99 award at University of Texas at Austin, where she worked before joining UCF in September of 2022. Fleeman says research into resistant infections must continue because they pose such a threat to health. "It is estimated that by 2050, antibiotic resistant bacterial infections will be the number one cause of human deaths," she says. "Our work is focused on preparing for this post-antibiotic era battle, where common antibiotics that we take for granted will no longer be effective, jeopardizing cancer therapy, organ transplants, and any modern medical advancement that relies on effective antibiotic therapies."