Cellular stress and coagulation factor production: when more is not necessarily better

Area of Science:

• Hematology
• Gene Therapy
• Molecular Biology

Background:

• Hemophilia A (HA) and B (HB) treatments evolved from plasma-derived factors to recombinant proteins and gene therapy.
• Adeno-associated viral vector (AAV) gene therapy is approved for HA and HB, but durability and safety are concerns.

Purpose of the Study:

• To review current understanding of factors limiting Factor VIII (FVIII) secretion in hepatocytes.
• To explore potential pathophysiological consequences of FVIII expression in hepatocytes.

Main Methods:

• Review of scientific literature on hemophilia A, FVIII protein, gene therapy, and hepatocyte biology.
• Analysis of challenges associated with FVIII protein folding, secretion, and cellular stress responses.

Main Results:

• FVIII, unlike FIX, is a large protein prone to misfolding and poor secretion.
• B-domain deleted FVIII, used in gene therapy, also exhibits inefficient secretion and can trigger the unfolded protein response.
• Unfolded protein response activation in hepatocytes poses risks including impaired function, survival, and potential oncogenesis.

Conclusions:

• Inefficient FVIII secretion and associated cellular stress are major hurdles for effective HA gene therapy.
• Further research is needed to overcome FVIII secretion limitations and ensure the safety and durability of gene therapy for hemophilia A.