What is the mechanism of Valoctocogene roxaparvovec?

Valoctocogene roxaparvovec is an innovative gene therapy developed for the treatment of hemophilia A, a genetic disorder characterized by the deficiency of clotting factor VIII (FVIII). This medication has been designed to provide a long-term therapeutic effect by addressing the underlying cause of the disease, rather than just managing its symptoms. The mechanism of action of Valoctocogene roxaparvovec involves several key steps which enable the production of functional FVIII within the patient’s body.

The therapy consists of an adeno-associated virus serotype 5 (AAV5) vector that has been engineered to carry a functional copy of the FVIII gene. The AAV5 vector is chosen for its ability to effectively target liver cells, which are the primary site for the natural production of FVIII in the body. The first step in the mechanism of Valoctocogene roxaparvovec involves the administration of the viral vector through intravenous infusion, ensuring systemic delivery.

Once administered, the AAV5 vector circulates through the bloodstream and targets the liver cells, also known as hepatocytes. The vector binds to specific receptors on the surface of these cells, facilitating its internalization. Upon entering the hepatocytes, the vector’s protein coat is degraded, allowing the release of the genetic material it carries.

The released DNA includes a promoter sequence and the B-domain deleted (BDD) version of the FVIII gene. The BDD form is utilized because it is smaller and more efficient for gene therapy applications, while still encoding a fully functional FVIII protein. The promoter sequence ensures that the gene is activated and transcribed within the liver cells.

Once the FVIII gene is transcribed into messenger RNA (mRNA), it is then translated into the FVIII protein by the cellular machinery. The newly synthesized FVIII protein undergoes post-translational modifications and is eventually secreted into the bloodstream, where it can perform its biological function of facilitating blood clot formation.

By providing a continuous source of FVIII directly from the patient’s liver cells, Valoctocogene roxaparvovec significantly reduces or even eliminates the need for regular exogenous FVIII infusions, which are typically required for hemophilia A patients. This gene therapy aims to maintain therapeutic levels of FVIII over an extended period, thereby improving the quality of life and clinical outcomes for individuals with hemophilia A.

In summary, Valoctocogene roxaparvovec’s mechanism of action involves the delivery of a functional FVIII gene to liver cells via an AAV5 vector, leading to sustained production of FVIII within the patient’s body. This innovative approach addresses the root cause of hemophilia A and offers a promising long-term treatment option for those affected by this genetic disorder.