The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy.
Studies on gene therapy for hemophilia B (HB) using adeno-associated viral (AAV) vectors showed that the safety of a given strategy is directly related to the vector dose. To overcome this limitation, we sought to test the efficacy and the risk of immunogenicity of a novel factor IX (FIX) R338L associated with ∼ 8-fold increased specific activity. Muscle-directed expression of canine FIX-R338L by AAV vectors was carried out in HB dogs. Therapeutic levels of circulating canine FIX activity (3.5%-8%) showed 8- to 9-fold increased specific activity, similar to humans with FIX-R338L. Phenotypic improvement was documented by the lack of bleeding episodes for a cumulative 5-year observation. No antibody formation and T-cell responses to FIX-R338L were observed, even on challenges with FIX wild-type protein. Moreover, no adverse vascular thrombotic complications were noted. Thus, FIX-R338L provides an attractive strategy to safely enhance the efficacy of gene therapy for HB.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jonathan D
JD
Finn
Timothy C
TC
Nichols
Nikolaos
N
Svoronos
Elizabeth P
EP
Merricks
Dwight A
DA
Bellenger
Shangshen
S
Zhou
Paolo
P
Simioni
Katherine A
KA
High
Valder R
VR
Arruda
D019943:Amino Acid Substitution; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000229:Dependovirus / Q000235:genetics; D004285:Dogs; D005164:Factor IX / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D002836:Hemophilia B / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006470:Hemorrhage / Q000235:genetics; D006801:Humans; D008297:Male; D009132:Muscles / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D000906:Antibodies; D005164:Factor IX