Program: Oral and Poster Abstracts
Session: 321. Blood Coagulation and Fibrinolytic Factors: Poster III
Clinical trials and preclinical studies in HB dogs have demonstrated that the therapeutic vector dose for AAV muscle gene therapy was a log higher than liver GT when direct multi-site intramuscular injection was used; however, intravascular delivery to the muscle allows the vector dose to be significantly reduced to 2-3 x 1012 vg/kg. Here, we used a regional peripheral transvenular injection of AAV serotype 6 to express cFIX-Padua in the skeletal muscle of HB dogs. These dogs are at high risk for inhibitor formation due to the null mutation in their canine F9 gene resulting in no mRNA or protein expression; typically, a single injection of cFIX wild-type protein (0.5 mg) results in the formation of a high titer inhibitor. Two adult dogs received gene therapy with 3 x 1012 vg/kg of AAV6-cFIX-Padua under the control of a CMV promoter. One dog (Malani) reached a plateau of 80-100% circulating cFIX activity levels with a follow-up time of 10 months (ongoing). Sustained antigen levels are 7-10%, resulting in ~10-fold higher specific activity than wild type FIX. The second dog (Una) achieved 45-60% sustained activity with corresponding 4-5% antigen levels (~11-fold increase in specific activity) after 14 months (ongoing observation). Neither dog has developed inhibitors to cFIX. Both dogs are also negative for non-neutralizing IgG1 and IgG2 against cFIX. Whole blood clotting time and thromboelastogram parameters have also normalized in both dogs. Notably, immune tolerance has been maintained despite challenge with 0.5 mg of cFIX-wild type protein. Together, these data support the use of skeletal muscle as a target tissue for the expression of FIX Padua and, in contrast to an early direct AAV-FIX intramuscular injection trial, patients with null mutations can now be enrolled. This is the first demonstration of complete correction of HB in large animal models using AAV gene therapy targeting the skeletal muscle and supports the feasibility and safety for potential clinical studies.
Disclosures: Arruda: Spark Therapeutics: Patents & Royalties ; Pfizer: Consultancy , Patents & Royalties , Research Funding .
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