University of Pittsburgh scientists along with international colleagues have identified a novel gene variant, PNPLA3 rs738409, and the subsequent biological pathway responsible for the development of metabolic associated fatty acid liver disease (MAFLD). Identification of this pathway to liver disease allows for development of pharmacological, nutritional, and gene therapies to compensate. The PNPLA3 rs738409 gene variant increases biological aberrant reactions in liver cells, leading to programmed cell death through an iron-dependent process called ferroptosis.
Description
The PNPLA3 rs738409 gene variant increases the risk of MAFLD, which can lead to cirrhosis and end-stage liver disease (ESLD). Furthermore, the variant, when present in a donor, can lead to ESLD in liver transplant recipients. The presence of PNPLA3 rs738409 gene variant in a liver graft is associated with development of MALFD and reduced long term post operative survival. Identification of this gene variant and its role in cell death, highlights a novel therapeutic target for the treatment of liver disease.
Applications
• Liver disease and cirrhosis
• End stage liver disease
• Liver transplantation
Advantages
The mechanisms that lead to the development of MAFLD are poorly understood, so treatment can be challenging. As MAFLD develops, it can lead to end stage liver failure requiring transplantation. In liver transplants, the presence of PNPLA3 rs738409 in donor liver grafts is associated with development of MAFLD and reduced postoperative 5-year survival. The gene variant PNPLA3 rs738409 leads to increased peroxisomal -oxidation and lipid peroxidation which can lead to cell death via ferroptosis, a form of iron-dependent cell death. Therapeutic interventions through multiple modalities including pharmacological, nutritional, and gene therapy, could decrease programmed cell death and alleviate the harmful outcomes caused by the variant.
Invention Readiness
Following genotyping of ESLD and living donors, the PNPLA3 rs738409 variant with its link to liver disease and poor survival was identified. In vitro studies using a pharmacological (deferoxamine, an FDA-approved iron chelator), nutritional (reduced L-glutathione), or gene therapy approach (increasing GPX4-expression using a viral vector), inhibited ferroptosis and reduced cell death. Further work is required to develop personalized treatment of patients to prevent the development of ESLD. Additionally, in living donors, genetic screening could increase survival in organ or tissue recipients.
IP Status
https://patents.google.com/patent/WO2025038398A1
