Mois : juin 2024

Researchers publishing in Cell Stem Cell have demonstrated that genetically diseased liver cells can be taken from human beings, altered in the laboratory, and used to regrow the livers of model mice.

Recreating an entire organ has its own difficulties

These researchers begin their paper by discussing existing cellular therapies for multiple tissues, such as bone, cornea, and even the entire skin of a seven-year-old with a life-threatening genetic disease [1]. However, internal organs have their own problems, most notably immunorejection, in which the immune systems of the recipient reject the new organ as foreign material. While transplantation of liver cells from person to person is possible, immunorejection, even with immunosuppressants, makes this a risky proposition [2].

Normally, to regrow an organ through a cellular therapy, a patient’s own cells are the best choice if it all possible; however, if these cells have a genetic disease, repopulating an organ with them would not be beneficial. If those cells could be genetically modified to cure this disease at its root, however, the repopulating cells would form a healthy organ while staying untargeted by the patient’s immune system.

The liver, which has greater regenerative capacity than any other human organ, is the low-hanging fruit for this approach, which has already been demonstrated to work in pigs [3]. While some work has been done on creating cells that are like liver cells (hepatocytes), those cells did not proliferate enough to be beneficial [4]. Other genetic approaches have also been found to be inefficient and impractical [5].

A CRISPR and AAV-based approach

Returning to well-studied genetic approachers, these researchers appear to have found a solution. First, they took hepatocytes derived from patients with genetic diseases and used an enhanced medium to cultivate these diseased cells. Then, using an adeno-associated virus (AAV) based on CRISPR-Cas9 biotechnology [6], they genetically altered these cultured cells.

This approach was not perfect, and there were some off-target effects, but it was substantially effective. Only a quarter of the cells ultimately expressed the desired genes, but after purification, three-quarters of the cells were expressing them.

These cells were then injected into a mouse model of liver disease, specifically human tyrosinemia type 1, which leads to liver failure. Two negative controls were used: untreated mice and mice given unmodified cells from diseased human donors. Every one of these controls was dead within five months. Another control group was of mice that received cells from healthy human donors. 8 out of 11 of those mice survived after 6 months. Of the mice that received the genetically engineered cells that had originally come from diseased human donors, 7 out of 11 of them had survived for 6 months.

Biomarkers confirmed this result. Although the edited cells were not exactly as effective as cells derived from healthy donors, many markers of liver function were very similar, including bilirubin and albumin. The researchers believe that these cells took longer to mature and populate than cells derived from healthy donors, but they still allowed most of the mice to survive. Further work confirmed that these cells are indeed capable of repopulating the organ.

This study stopped just short of an actual clinical trial. The genetically altered hepatocytes were shown to proliferate in mice; the next step is to have them proliferate in human patients who wish to see if their genetic disorders may have an effective treatment. Additionally, genomic instability is a hallmark of aging; if it is possible to modify and purify hepatocytes derived from aged donors, and repopulate their livers with these modified and proliferating cells, many age-related liver issues may have an effective treatment.

Literature

[1] Hirsch, T., Rothoeft, T., Teig, N., Bauer, J. W., Pellegrini, G., De Rosa, L., … & De Luca, M. (2017). Regeneration of the entire human epidermis using transgenic stem cells. Nature, 551(7680), 327-332.

[2] Jorns, C., Nowak, G., Nemeth, A., Zemack, H., Mörk, L. M., Johansson, H., … & Ericzon, B. G. (2016). De novo donor‐specific hla antibody formation in two patients with Crigler‐Najjar syndrome type I following human hepatocyte transplantation with partial hepatectomy preconditioning. American Journal of Transplantation, 16(3), 1021-1030.

[3] Hickey, R. D., Mao, S. A., Glorioso, J., Elgilani, F., Amiot, B., Chen, H., … & Nyberg, S. L. (2016). Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1. Science translational medicine, 8(349), 349ra99-349ra99.

[4] Gao, Y., Zhang, X., Zhang, L., Cen, J., Ni, X., Liao, X., … & Hui, L. (2017). Distinct gene expression and epigenetic signatures in hepatocyte-like cells produced by different strategies from the same donor. Stem Cell Reports, 9(6), 1813-1824.

[5] VanLith, C. J., Guthman, R. M., Nicolas, C. T., Allen, K. L., Liu, Y., Chilton, J. A., … & Hickey, R. D. (2019). Ex vivo hepatocyte reprograming promotes homology‐directed DNA repair to correct metabolic disease in mice after transplantation. Hepatology Communications, 3(4), 558-573.

[6] Zhang, K., Zhang, L., Liu, W., Ma, X., Cen, J., Sun, Z., … & Hui, L. (2018). In vitro expansion of primary human hepatocytes with efficient liver repopulation capacity. Cell stem cell, 23(6), 806-819.

A team of researchers has found that corylin, a compound previously investigated for its anti-senesence properties, is effective against osteoporosis in a mouse model.

A return to a well-known compound

Corylin is a compound that was first discovered in Psoralea corylifolia, a plant commonly used in Chinese traditional medicine. This is far from the first investigation into corylin: this compound has been found to be effective against a few aspects of aging in cellular, yeast, and mouse models. These researchers also cite prior studies demonstrating its potential utility against inflammation [1], oxidative stress [2], and cancer [3].

For this study, however, their main interest is its effects on bone. Corylin has been previously reported to encourage bone-building cells (osteoblasts) [4] while suppressing bone-consuming cells (osteoclasts) [5]. This might fight back against osteoporosis, a condition in which osteoclasts run wild and consume substantial amounts of bone material, rendering bones brittle and falls potentially deadly.

Discourages osteoclasts at every level

This study’s experiments began with bone marrow macrophages derived from young mice. These cells are known to differentiate into osteoclasts when treated with the compound RANKL. However, co-treatment with corylin blocked most of this differentiation in a dose-dependent manner.

Similarly, treating existing osteoclasts with corylin decreased their capabilities, preventing them from creating deep pits when placed on bone plates. These results were corroborated with a gene expression analysis, which reported that genes related to osteoclast differentiation and function were inhibited by corylin. Additionally, the osteoclast differentation process, in which pre-osteoclasts migrate and fuse into osteoclasts, was disrupted. This was found to be accompanied by a reduction in mitochondrial mass and number.

Following these results, the researchers continued with a mouse study. 12-week-old female mice had their ovaries removed, which leads to overproduction of osteoclasts and severe osteoporosis. Treating this population with corylin for four weeks after the surgery reduced much of the osteoclast production and bone loss, although not to the level of the control group.

These results, while initially promising, were not conducted in wild-type mice or on cells derived from human beings. Given the amount of information published on corylin, more comprehensive animal and human trials are warranted to determine its side effects and prove or disprove its efficacy against multiple conditions, including osteoporosis. The precise mechanism of action should also be investigated.

Literature

[1] Chen, C. C., Li, H. Y., Leu, Y. L., Chen, Y. J., Wang, C. J., & Wang, S. H. (2020). Corylin inhibits vascular cell inflammation, proliferation and migration and reduces atherosclerosis in ApoE-deficient mice. Antioxidants, 9(4), 275.

[2] Wei, S. M., Yan, Z. Z., & Zhou, J. (2011). Psoralea corylifolia protects against testicular torsion/detorsion-induced ischemia/reperfusion injury. Journal of ethnopharmacology, 137(1), 568-574.

[3] Lin, Z., Liao, L., Zhao, S., Gu, W., Wang, G., Shen, Z., … & Yan, T. (2023). Corylin inhibits the progression of Non-small cell lung cancer cells by regulating NF-κB signaling pathway via targeting p65. Phytomedicine, 110, 154627.

[4] Yu, A. X. D., Xu, M. L., Yao, P., Kwan, K. K. L., Liu, Y. X., Duan, R., … & Tsim, K. W. K. (2020). Corylin, a flavonoid derived from Psoralea Fructus, induces osteoblastic differentiation via estrogen and Wnt/β‐catenin signaling pathways. The FASEB Journal, 34(3), 4311-4328.

[5] Yu, A. X. D., Xiao, J., Zhao, S. Z., Kong, X. P., Kwan, K. K. L., Zheng, B. Z. Y., … & Tsim, K. W. K. (2021). Biological evaluation and transcriptomic analysis of Corylin as an inhibitor of osteoclast differentiation. International Journal of Molecular Sciences, 22(7), 3540.

Hevolution, the Saudi-funded longevity non-profit behemoth, has been around for about two years, and it hasn’t been wasting any time, funding research and investing in biotech companies. With its yearly budget touching 1 billion dollars, Hevolution is the biggest non-profit donor and one of the most important players in the longevity field today.

Hevolution touts a holistic approach by working across the “longevity ecosystem”, which includes everything from influencing public opinion to funding fundamental research into aging biology. For now, however, Hevolution mostly focuses on the latter.

Hevolution is also the organizer of the Global Longevity Summit in Riyadh. The first one, which was held earlier this year, attracted a record 1,500 participants. The next one will be held in February 2025.

Hevolution’s CEO, Dr. Mehmood Khan, is a charismatic leader with a trove of experience in some of the biggest companies in the world. He is also an MD specializing in endocrinology and a long-time longevity enthusiast.

Tens of millions in new grants

At a press conference today, Hevolution announced a funding milestone of over $400 million in investments in healthspan over the past 21 months along with a new round of grants.

A $20.2 million grant will be awarded to Albert Einstein College of Medicine for research focused on senescence and aging. The research will be led by Dr. Ana Maria Cuervo, a leader in the aging field and a member of the National Academy of Sciences.

“This is one of the most exciting times in the research on the biology of aging, due to the multiple experimental proofs that show we can modulate the way organisms age. However, we all fear that the scarcity of funding may hinder progress,” Cuervo said. “Timely support through the many programs of the Hevolution Foundation will be key to recruiting and retaining new talent in this field, maintaining momentum, and accelerating the discovery and implementation of gerotherapeutic interventions to ensure healthy aging.”

Northwestern University will receive a $32.3 million grant for proteostasis research led by Dr. Richard Morimoto, Bill and Gayle Cook Professor of Biology at Northwestern University. Loss of proteostasis (the regulation of the concentration, conformation, binding interactions, and location of individual protein molecules within a cell) is one of the hallmarks of aging.

“We are thrilled that the Proteostasis Consortium is partnering with the Hevolution Foundation to address this fundamental question on the biology of aging,” Morimoto said. “Our team, including researchers at Northwestern, the University of California San Francisco, the Gladstone Institute of Neurological Disease, Stanford, Scripps Research, Harvard Medical School, and the Health Research Institute of Asturias, is working to provide new insights on the molecular biology of healthy aging and develop approaches to rejuvenate cellular and organismal health.”

Also announced today were a series of grant programs to support individual geroscience researchers, including:

Hevolution Foundation Postdoctoral Training in Geroscience (HF-PTG), which will invest a total of $5 million over four years (recently began accepting applications)
Hevolution Foundation Geroscience Research Opportunities (HF-GRO), providing up to $25 million in 2024 to fund projects in aging biology or geroscience (round two recently began accepting applications)
Hevolution Foundation Geroscience in Latin America (HF-GLA), a pilot initiative providing up to $5M over four years to researchers in Latin America (will begin accepting applications in July)

Towards active prevention

Khan also touched on Hevolution’s vision. “We’re spending a decade of life in poor health — this is a decade too many,” he said. “Our current healthcare system focuses more on intervention, but our goal is to address the underlying causes of aging and age-related diseases. Geroscience and healthspan science are critically underfunded, which is why Hevolution is stepping up to bridge this gap. We are proud to be the world’s largest philanthropic funder in geroscience.”

Khan emphasized the immense economic and societal impact of populational aging, which will soon start straining global resources if we don’t find a way to extend healthy lifespan. The current reactive approach to healthcare is not producing additional gains in lifespan despite growing expenses. Hevolution’s vision for solving this is to move the global focus towards active prevention.

Population graying is a universal trend, Khan said, as all regions are getting older, including those that are relatively young today. Underdeveloped regions are particularly vulnerable because they lack the resources and the infrastructure needed to support their aging populations. “Estimates suggest that Africa will have more old people than any other continent in the world, given time,” Khan said. However, those regions also have more time to prepare and could produce the greatest impact in terms of healthy years of life.

Investments in biotech

To date, Hevolution has invested in two longevity biotech companies. Aeovian Pharmaceuticals is working on a selective mTORC1 inhibitor, while Rubedo Biosciences is focused on senolytics. Answering a question from Lifespan.io, Khan said that this choice does not necessarily reflect Hevolution’s affinity towards any particular direction in aging research: “I don’t have a favorite child. We look at the usual things – the quality of the science, the management team, and the success that they’ve had, including the data that they present. I can tell you we’ve looked so far at about 200.” Khan promised new investment announcements soon.

Advocacy matters

We also asked Khan whether Hevolution has been active in the field of longevity advocacy, which the foundation itself sees as a crucial element of the longevity ecosystem. Khan confirmed that the company assigns high importance to advocacy and suggested that because of its sheer size and visibility, Hevolution has already contributed a lot to shifting the attention of the world’s decision makers towards aging. Khan has been talking to prominent government and business leaders, and he sees healthy aging “becoming a priority.”

“It’s not just Hevolution,” he said. “The work you’re doing, everybody’s doing – if this activity is somewhat synchronized and aligned on the terminologies we use, it will raise the bar, and we’re seeing evidence that that is the case.”