Periodic Reporting for period 1 - NASHTARGET (Validation of a new drug target in non-alcoholic steatohepatitis)
Periodo di rendicontazione: 2023-06-01 al 2024-11-30
The prevalence of metabolic liver disease is rising sharply, mainly driven by the causal connections between obesity, diabetes, and non-alcoholic steatohepatitis (NASH). In the absence of approved treatments, NASH represents a clear unmet medical need and an enormous economic burden for society. The development and progression of NASH is to a large extent driven by oxidative stress, originating from metabolism of excess fat. Reactive Oxygen Species (ROS) and other reactive metabolic byproducts stimulate pathological signaling through the MAP kinases (MAPK) p38 and JNK, which drive the inflammatory and fibrotic hallmarks of NASH. As a result, p38 and JNK inhibitors have been widely explored as treatments against ROS-driven diseases by the pharmaceutical industry. These efforts have been largely futile due to the multiplex biological roles of these kinases. Instead, inhibition of upstream ROS-sensing kinases hold promise for introduction of new treatment principles. An example is the ASK1 inhibitor selonsertib, which has been tested in NASH patients with limited effects. In my ERC Consolidator project “PHYRIST”, we discovered that the MAPK activating kinase ZAK also controls p38 and JNK upon oxidative stress. We showed that the impact of this signaling is especially prominent in the liver, and that ZAK knock-out (KO) mice were protected against the development of liver steatosis and mild fibrosis when fed a high fat/high sugar (HFHS) diet for 25 weeks. There is thus a good rationale for pursuing ZAK as a drug target for NASH and other metabolic diseases. In the project “NASHTARGET”, I investigated whether ZAK KO mice, either alone or in combination with ASK1 KO, were similarly protected against developing NASH-like disease when fed a recently developed and superior induction diet for only 12 weeks.
To establish a role for ZAK in NASH development and explore the potential of this kinase as a drug target, we compared liver pathology induced by HFHS diet (25 weeks) and a more aggressive induction diet based on animal fat (12 weeks). The latter diet is composed to more precisely mimick an unhealthy western diet compared to more standard experimental obesogenic diets such as HFHS. We interrogated WT, ZAK KO, ASK1 KO and double-KO mice. We were able to confirm the metabolic protection offered by ZAK ablation on HFHS. The more aggressive diet induced massive liver fibrosis (stage 2, 3 and 4), and in this setting the ZAK KO mice were not protected. In fact, the severity of fibrotic hallmarks was similar between the four mouse genotypes.
Translatability of murine disease models to human conditions is notoriously difficult. This is especially true in the space of NASH and liver disease. Several drug candidates have been taken forward to clinical studies based on positive results in these kinds of mouse models, only to fail due to lack of efficacy in humans. While we got positive results with a mild induction model (HFHS), we did not observe any effect of ZAK ablation with a more aggressive model. In conclusion, we posit that it will be difficult to close the translational gap in this case with limited mechanistic insight into how ZAK and its downstream kinases p38 and JNK impact on liver fibrosis in humans.
Translatability of murine disease models to human conditions is notoriously difficult. This is especially true in the space of NASH and liver disease. Several drug candidates have been taken forward to clinical studies based on positive results in these kinds of mouse models, only to fail due to lack of efficacy in humans. While we got positive results with a mild induction model (HFHS), we did not observe any effect of ZAK ablation with a more aggressive model. In conclusion, we posit that it will be difficult to close the translational gap in this case with limited mechanistic insight into how ZAK and its downstream kinases p38 and JNK impact on liver fibrosis in humans.
Based on our published academic work and the experimental results from NASHTARGET, we believe that there is still a potential medical case for targeting ZAK and/or its downstream kinases as a treatment against NASH. More mechanistic insight into the signaling from these kinases to key fibrotic mediators will be needed to close the present knowledge gap.