Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates

Abstract

Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

“…Inactivation of c-FLIP L in mouse hepatocytes promotes liver injury triggered by death receptor agonists (39). A recent study demonstrated that AAV-mediated overexpression of c-FLIP L in the liver ameliorates NASH in mice and nonhuman primates (41), illustrating a crucial role of this factor in NASH. However, the physiological and pathophysiological cues that impinge on c-FLIP L remain largely unknown.…”

Impact of neutralizing antibodies against AAV is a key consideration in gene transfer to nonhuman primates

“…However, the overall experimental design for the cited studies 1–4,9 in this correspondence challenges the conventional doctrine of previous findings on pre-existing NABs against AAV virus. For example, in the above studies in question, it was not stated whether any of the monkeys were screened for AAV8 NABs.…”

“…Recently, Hongliang Li and colleagues 1–4 published four studies in Nature Medicine applying AAV serotype 8 vectors (AAV8) in nonhuman primate (NHP) models of nonalcoholic steatohepatitis. In each study, genes delivered to the liver via AAV vectors demonstrated transduction in these large animal models, and therapeutic effects were achieved.…”

“…In an unpublished study, we found that 4% of 120 monkeys were seronegative for the AAV8 NAB (data not shown). It should also be noted that the probability of NAB occurrence should actually be higher in older animals, such as those used in these studies (aged 8–9 years) 1–4 , as they are more likely than younger animals to have been exposed to AAV8 and other AAV serotypes in their lifetime. Furthermore, in animals or humans lacking pre-existing NABs, the vector cannot be readministered (unless a different viral capsid is chosen) owing to potent NAB responses that occur within days after the initial exposure to vector, which can persist for months.…”

Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis

“…Recent phase II data demonstrated reduction of fibrosis without worsening of steatohepatitis after only 24 weeks of GS-4997 treatment in NAFLD patients (76). Caspase-8 and FADD-like apoptosis regulator (CFLAR) has been identified as a key suppressor of NASH that directly blocks ASK1/JNK1 activation (77). Therefore, CFLAR-mimicking drugs represent a novel therapeutic option for fatty liver disease.…”