Mois : septembre 2024

Ora Biomedical, Inc., a pioneering longevity biotechnology company, is pleased to announce that it has been awarded a Small Business Innovation Research (SBIR) Phase I grant from the National Institutes of Health (NIH). The $324,240 grant will support the development of EleGantry, an innovative software and hardware infrastructure designed to enhance rigor and reproducibility in invertebrate research, with a particular focus on longevity studies using Caenorhabditis elegans (C. elegans).

EleGantry: Revolutionizing Preclinical Drug Discovery

Ora Biomedical specializes in discovering and developing interventions that extend healthy lifespan and combat age-associated diseases by targeting the fundamental mechanisms of biological aging. The EleGantry system represents a significant advancement in the company’s high-throughput drug discovery pipeline. By automating key steps in the C. elegans research process and enhancing data collection across the entire lifespan, EleGantry will address the growing need for increased rigor and reproducibility in preclinical studies.

“With the NIH’s support, we are poised to identify and overcome major sources of variability and challenges associated with C. elegans research, contributing to our goal of creating the world’s largest and highest quality longevity interventions database,” said Dr. Mitchell Lee, CEO of Ora Biomedical. “EleGantry will not only elevate the standard of preclinical aging research but also
expedite development of robust therapeutics that can significantly extend healthy human lifespan.”

Why EleGantry Matters

C. elegans has long been a mainstay in biomedical aging research because highly evolutionarily conserved features drive aging from invertebrates to mammals. However, variability in research methodologies has often led to inconsistent results, particularly in studies focused on lifespan. EleGantry will mitigate these issues by integrating advanced imaging, data collection, and analysis tools powered by state-of-the-art machine learning algorithms. The platform will also automate data reporting, making it easier for researchers to replicate studies and validate findings. Ora Biomedical’s pioneering work in this field advances non-mammal animal models for drug development and aligns closely with the FDA Modernization Act 2.0 which aims to reduce the use of live mammals in research.

“The development of EleGantry is crucial as we move towards more reliable and scalable invertebrate models for drug discovery,” added Dr. Lee. “This tool will enable us to identify and prioritize therapeutic leads with unprecedented efficiency and accuracy.”

Looking Ahead

The successful completion of this Phase I project will pave the way for the subsequent development and commercialization of EleGantry, further establishing Ora Biomedical as a leader in longevity biotechnology. The company plans to use EleGantry to expand its preclinical screening capabilities, providing a robust platform for discovering the next generation of gerotherapeutics. This project is supported by the Office Of The Director, National Institutes Of Health and the National Institute of General Medical Sciences (NIGMS), under Award Number R43OD037622. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About Ora Biomedical

Ora Biomedical, Inc. is a longevity biotechnology company headquartered in Tukwila, WA. Launched out of the University of Washington School of Medicine in 2022, Ora Biomedical develops interventions that maximize healthy lifespan by targeting the molecular mechanisms that drive aging itself. Ora uses best-in-class robotics and AI to perform high-throughput, high-precision phenotypic testing in live animals with lifespan, healthspan, and stress resistance as primary endpoints.

www.orabiomedical.com

Company Press Contact:

Dr. Mitchell Lee

CEO & Co-Founder, Ora Biomedical, Inc.

Email: mitchell@orabiomedical.com

In a new study, a multi-prong treatment combined with a clever delivery method has shown promise against one of the deadliest cancers [1].

Lethal and barely treatable

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. It is rarely diagnosed early and very aggressive. It also responds poorly to treatment, primarily because its fibrotic tumor microenvironment (TME) hinders infiltration by immune cells.

Overall, the five-year survival rate for pancreatic cancer is slightly above 10%. Even for patients who were diagnosed early, it stands at just 37%, making this a high-priority target for cancer researchers.

One novel approach involves inducing senescence in cancer cells [2], causing them to produce the senescence-associated secretory phenotype (SASP). SASP factors are highly inflammatory, which helps remodel the TME and increase its susceptibility to infiltration by immune cells.

This approach works reasonably well in some cancer types. However, in PDAC, TME suppresses proinflammatory SASP components and the immune system activation that they are supposed to trigger.

The immune response can be bolstered by activating the stimulator of interferon genes (STING) pathway. This increases production of interferon and some other pro-inflammatory cytokines [3]. STING agonists showed some promise against PDAC, but their use is limited by their poor uptake by cells and short half-life (they are excreted quickly). The pancreas is also very hard to reach for direct intratumoral delivery.

Multiple approaches

In this study published in Science Translational Medicine, scientists from the University of Massachusetts tested a novel combination therapy in a mouse model of PDAC. One element of the combination consisted of two drugs: a STING agonist and a toll-like receptor 4 (TLR4) agonist. TLR4 agonists can additionally stimulate interferon responses. The other half was a popular duo of senescence-inducing compounds, trametinib and palbociclib (T/P).

Importantly, the STING agonist cdGMP and the TLR4 agonist MPLA were encapsulated together in nanoparticles (NPs) to overcome the usual delivery limitations. Achieving this was not an easy task since cdGMP is hydrophilic and TLR4 is hydrophobic. The researchers solved this problem by loading the two molecules into different compartments: cdGMP into the aqueous NP core and MPLA into the lipid bilayer shell.

Although NPs were administered intravenously, they found their way to the tumor area and infiltrated numerous cell types, including macrophages and antigen-presenting dendritic cells. NPs hardly accumulated in organs and did not cause toxicity.

Just as the researchers hoped, combining NPs with the pro-SASP treatment led to a synergistic effect. Pretreatment with the senescence-inducing duo T/P for 12 days increased the uptake of NPs by both tumor cells and immune cells. Moreover, it worked both ways: SASP induction was stronger with the combination therapy than with T/P alone.

“Together,” the paper says, “these findings demonstrate that combinatorial T/P and immuno-NP treatment, through both tumor cell autonomous and non–cell autonomous molecular mechanisms, enhances IFN signaling, proinflammatory cytokine production, and antigen presentation in the PDAC TME.”

An encouraging proof of concept

However, the important test is the therapy’s anti-tumor effectiveness. Here, too, the combination was more effective than NP or T/P treatments alone, leading to massive tumor necrosis in just 48 hours and significantly improved survival times. Moreover, some mice had complete response (full eradication of tumors), although the cancer returned after the treatment stopped.

“This is pretty striking,” said Marcus Ruscetti, assistant professor of molecular, cell and cancer biology at UMass Chan Medical School, and a corresponding author on the study. “We’ve never seen that in this model before.”

Ruscetti said that although all animals eventually succumbed to cancer, the results still were “a very encouraging step toward a cure.”

“If you go beyond pancreas cancer to other cancer types, you need a combination therapy to target the tumor and the immune system,” he added. “This is a strategy to be able to do that.”

Collectively, our results suggest that engineering approaches to target multiple cell types and immune suppressive barriers through induction of type I IFN signaling in the PDAC TME could pave the way for coordinated innate and adaptive immune responses to achieve immunotherapy successes that have thus far been elusive for patients with PDAC.

Literature

[1] Chibaya, L., DeMarco, K. D., Lusi, C. F., Kane, G. I., Brassil, M. L., Parikh, C. N., … & Ruscetti, M. (2024). Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer. Science Translational Medicine, 16(762), eadj9366.

[2] Ruscetti, M., Morris, J. P., Mezzadra, R., Russell, J., Leibold, J., Romesser, P. B., … & Lowe, S. W. (2020). Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell, 181(2), 424-441.

[3] Vonderhaar, E. P., Barnekow, N. S., McAllister, D., McOlash, L., Eid, M. A., Riese, M. J., … & Dwinell, M. B. (2021). STING activated tumor-intrinsic type I interferon signaling promotes CXCR3 dependent antitumor immunity in pancreatic cancer. Cellular and molecular gastroenterology and hepatology, 12(1), 41-58.

In Aging, researchers have described how a derivative of caffeic acid inhibits osteoclasts, the cells that break down bone.

A modification of a tested compound

We have recently published new information on what triggers the imbalance between bone-destroying osteoclasts and bone-building osteoblasts. This is a well-known problem with aging, and researchers around the world have looked into ways of rectifying this imbalance. Caffeic acid, which is found in coffee, tea, fruits, vegetables, and some extracts, has, among other positive effects, been previously found to suppress osteoclasts [1], including in a rat study [2].

These researchers have previously modified caffeic acid into N-(4-methoxyphen) methyl caffeamide (MPMCA), a compound that they have found to be more effective than regular caffeic acid in protecting the liver against oxidative stress [3]. Therefore, they conducted this study in order to determine if it could also be more effective in suppressing osteoclast activity.

Broad effects against precursors and mature cells

Interestingly, MPMCA does not inhibit osteoclast precursors under normal circumstances at any of the tested doses, from 0.1 to 3 μM. However, when these precursors are stimulated to become osteoclasts through the RANKL pathway for seven days, MPMCA reduces the number of osteoclasts, markedly reduces their average size, and suppresses the production of F-actin, which is required for differentiated osteoclasts to attach to bone. These effects are dose-dependent.

Gene expression analysis confirmed these findings. The genes TRAP, CTSK, and NFATC1, all of which are related to osteoclast differentiation, were suppressed by MPMCA. Testing at higher doses, the researchers found that MAP kinase pathways were similarly suppressed, as was the well-known NF-κB pathway.

MPMCA also encouraged differentiated osteoclasts to die by apoptosis. Cleaved caspase-3 and DAP, both of which are apoptosis markers, were increased with MPMCA. Just like with precursors, both the number and size of these mature osteoclasts were reduced.

However, MPMCA, unlike caffeic acid [2], did nothing to osteoblasts. Osteoblast differentiation markers, including gene expression, were unaffected.

These findings are very positive, but they were only in cells. If the results of this study can be replicated, and this compound can be confirmed to be safe and effective in animal models, MPMCA may be a candidate for clinical trials against osteoporosis and age-related bone loss.

Literature

[1] Ekeuku, S. O., Pang, K. L., & Chin, K. Y. (2021). Effects of caffeic acid and its derivatives on bone: A systematic review. Drug design, development and therapy, 259-275.

[2] Tang, Q. Y., Kukita, T., Ushijima, Y., Kukita, A., Nagata, K., Sandra, F., … & Iijima, T. (2006). Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats. Histochemistry and cell biology, 125, 215-225.

[3] Tsai, T. H., Yu, C. H., Chang, Y. P., Lin, Y. T., Huang, C. J., Kuo, Y. H., & Tsai, P. J. (2017). Protective effect of caffeic acid derivatives on tert-butyl hydroperoxide-induced oxidative hepato-toxicity and mitochondrial dysfunction in HepG2 cells. Molecules, 22(5), 702.