Research foci Cell and Gene Therapy
Hereditary metabolic liver diseases
The scientists of the Guest Research Group Cell- and Gene Therapy currently study cell- and gene based methods to correct hereditary liver diseases such as urea cycle defects or Crigler-Najjar syndrome Type I. Protocols have been developed to generate hepatocytes from gene corrected induced pluripotent stem (iPS) cells or through direct reprogramming methods. Transplantation of those cells will require clinically applicable liver repopulation methods, which allow controlled ablation of endogenous hepatocytes and expansion of transplanted cells. The researchers currently test several promising methods to achieve partial repopulation and definitive correction of disease phenotypes. More recently, a novel method for in vivo reprogramming of (myo-)fibroblasts into hepatocytes has been developed. Application of this technique resulted in therapeutic reduction of liver scarring in chronic liver disease.
Another approach focuses on direct in vivo genome editing of disease causing genes by CRISPR-CAS-9 and Zinc finger based methods in combination with homologous recombination. The group has developed an “all in one” AAV based vector for in vivo correction of the liver phenotype in mice with hereditary tyrosinemia.
For transient therapy of urea cycle defects we develop RNA based gene correction in combination with non-viral delivery systems.
Acute liver failure
Acute liver failure can occur in healthy persons and is triggered by fatal infections or drug (antibiotics, pain killers) toxicity. In cooperation with research groups from the cluster of excellence “Rebirth” the scientists have recently identified a microRNA, which interferes with apoptotic and necrotic pathways and restores glutathione stores in hepatocytes. Therapeutic application of a stabilized variant of the microRNA resulted in improved survival after induction of acute liver failure. In their next experiments the patented therapy will be optimized for appropriate dosage and timing. Additionally, more microRNAs from screening experiments will be evaluated for synergistic effects in acute liver failure. Hepatocyte targeted delivery with non-viral vectors will be established and optimized. Depending on results of these experiments a clinical trial in patients with acute liver failure is planned.
Chronic liver diseases
In persistent chronic liver injuries such as hepatitis B or C virus infection, hepatic stellate cells become activated and transform into myofibroblasts. The production of extracellular matrix proteins results in fibrosis and scarring of the liver. Technologies, which aim to reduce the number of myofibroblasts or their activation status, would thus be useful for the therapy of liver fibrosis and cirrhosis. The researchers could recently show that the targeted expression of four transcription factors could convert hepatic myofibroblasts into hepatocytes in vivo. The reduction of myofibroblast numbers and de novo generation of hepatocytes improved liver fibrosis scores in mice. The next efforts will focus on non-viral and non DNA methods to target and reprogram the myofibroblast population in the liver.
The research group currently studies feasibility of generating of chimeric livers in rats and pigs for organ transplantation in patients with endstage liver diseases. Blastocyst injection of iPS cells results in low grade chimerism in “offspring” animals with a high degree of iPS derived hepatocytes in the liver, if a cellular niche is provided. In a rat model chimeric livers will then be transplanted into a disparate host animal. They will study cellular adaption and immunological acceptance of the transplanted organ in the absence of immunosuppression. Pigs with a liver niche, which allows a high degree of hepatocellular chimerism, have been generated in cooperation with the Institut für Nutztiergenetik (FLI) in Mariensee. The generation of monkey / pig liver chimeras is planned as “proof of principle” studies for human applications.
Hereditary metabolic liver diseasesr
Cantz T, Sharma AD, Ott M (2014) Concise Review: Cell therapies for hereditary metabolic liver diseases - concepts, clinical results and future developments. Stem Cells. doi: 10.1002/stem.1920.
Funding: DFG OT131/6-1
Acute liver failure
Yang D, Yuan Q, Balakrishnan A, Bantel H, Klusmann JH, Manns MP, Ott M, Cantz T, Sharma AD (2016) MicroRNA-125b-5p mimic inhibits acute liver failure. Nat Commun 7: 11916.
Chronic liver diseases
Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, Reetz J, Brandes S, Dai Z, Putzer BM, Arauzo-Bravo MJ, Steinemann D, Luedde T, Schwabe RF, Manns MP, Scholer HR, Schambach A, Cantz T, Ott M*, Sharma AD* (2016) Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis. Cell Stem Cell 18(6): 797-808. (*corresponding authors)
Funding: DFG-Koselleck: 131/7-1-3013879