Determining the Minimally Effective Dose of a Clinical Candidate Adeno-Associated Virus Vector in a Mouse Model of...

Area of Science:

• Gene Therapy
• Hematology
• Molecular Biology

Background:

• Hemophilia A is a genetic bleeding disorder caused by deficiency in human blood coagulation factor VIII (hFVIII).
• AAVhu37.E03.TTR.hFVIIIco-SQ.PA75 is a promising gene therapy vector candidate for hemophilia A.
• Determining the minimally effective dose (MED) is crucial for clinical translation.

Purpose of the Study:

• To establish the minimally effective dose (MED) of the AAVhu37.E03.TTR.hFVIIIco-SQ.PA75 gene therapy vector in a hemophilia A mouse model.
• To assess the safety and tolerability of varying doses of the gene therapy vector.

Main Methods:

• Mice with hemophilia A received intravenous injections of four different doses of the AAV vector (3 × 10¹¹ to 1 × 10¹³ genome copies/kg) or a vehicle control.
• Animals were monitored for hFVIII activity, anti-hFVIII antibodies, and safety parameters including liver enzymes and bilirubin.
• Histopathological examination of tissues was performed at days 28 and 56 post-administration.

Main Results:

• All vector doses successfully restored hFVIII activity, indicating the MED is the lowest dose tested (3 × 10¹¹ GC/kg).
• No dose-limiting safety markers were observed; the maximally tolerated dose exceeded the highest dose administered (1 × 10¹³ GC/kg).
• Minor elevations in total bilirubin were noted at higher doses on day 56, but no significant vector-related adverse findings were detected.

Conclusions:

• The minimally effective dose for AAVhu37.E03.TTR.hFVIIIco-SQ.PA75 gene therapy in hemophilia A mice is 3 × 10¹¹ genome copies/kg.
• The gene therapy vector demonstrates a favorable safety profile, with no dose-limiting toxicities observed up to 1 × 10¹³ genome copies/kg.
• This study supports the potential of AAVhu37.E03.TTR.hFVIIIco-SQ.PA75 as a safe and effective gene therapy for hemophilia A.