Treating Genetic Liver Diseases at Their Root

The modified cells were comparable to naturally healthy cells.


Liver geneticsLiver genetics

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.


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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.

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[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.


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[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.


About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.