University of Pittsburgh researchers have synthesized antagonistic peptides to promote liver regeneration (LR).The tight junction protein junctional adhesion molecule A (JAM-A) has a role in regulating hepatocyte (HC) proliferation. Recently it was discovered that JAM-A can inhibit HC proliferation and genetic ablation of JAM-A promotes LR following liver injury. Building on this knowledge, antagonist peptides targeting JAM-A have been developed. These peptides can increase HC proliferation, enhancing the liver’s regenerative capacity. This novel strategy could revolutionize the treatment of liver disease improving the lives of millions worldwide.
Treatment with a JAM-A antagonistic peptide (peptide 1) can induce HC proliferation as indicated by significantly (* = p <0.05) increased Cyclin D1 and Ki67 transcript levels. This novel treatment approach for could remove the need for liver transplant in patients with severe life limiting liver disease.
Description
Liver failure leads to over 1.5 million deaths globally each year. Successful treatment of end-stage liver disease (ESLD) with liver transplantation can prevent many of these deaths. With a growing incidence of ESLD globally, there is a pressing clinical need to develop effective alternatives to transplantation. The liver is the only visceral organ in humans that can regenerate. The ability to regenerate is limited by chronic and acute liver disease. Understanding the mechanism of LR could lead to the discovery of therapeutic targets by antagonists or agonists to enhance or suppress key processes involved in LR. This novel approach targets JAM-A with an antagonist peptide, but future studies could uncover other targets to enhance LR and provide even more therapeutic strategies for patients with ESLD.
Applications
• Chronic liver disease
• Acute liver disease
• Acetaminophen-induced liver injury (AILI)
Advantages
While liver transplantation improves outcomes in patients with ESLD, a lack of available organs and post-operative complications including rejection and the need for lifelong immunosuppression therapy limits the availability and success of this treatment. Acetaminophen overdose is a common cause of acute liver failure (ALF) leading to AILI. Early treatment with N acetylcysteine within 8–10 hours of the overdose can restore liver function, but efficacy decreases in late presenting patients with many who develop ALF eventually requiring a liver transplant.
This approach uses an antagonistic peptide targeting JAM-A to enhance LR potentially removing the need for transplantation.
Invention Readiness
Following discovery of the role of JAM-A in inhibiting LR, two antagonistic peptides were produced. Peptide 1 was most effective in increasing HC proliferation as well as accelerating recovery in an animal AILI model.
IP Status
Patent Pending
