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Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII
- Source :
- Blood. 127:565-571
- Publication Year :
- 2016
- Publisher :
- American Society of Hematology, 2016.
-
Abstract
- Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder treated by infusion of fresh-frozen plasma, plasma-derived FVII concentrates and low-dose recombinant activated FVII. Clinical data suggest that a mild elevation of plasma FVII levels (10% normal) results in improved hemostasis. Research dogs with a G96E missense FVII mutation (FVII-G96E) have1% FVII activity. By western blot, we show that they have undetectable plasmatic antigen, thus representing the most prevalent type of human FVII deficiency (low antigen/activity). In these dogs, we determine the feasibility of a gene therapy approach using liver-directed, adeno-associated viral (AAV) serotype 8 vector delivery of a canine FVII (cFVII) zymogen transgene. FVII-G96E dogs received escalating AAV doses (2E11 to 4.95E13 vector genomes [vg] per kg). Clinically therapeutic expression (15% normal) was attained with as low as 6E11 vg/kg of AAV and has been stable for1 year (ongoing) without antibody formation to the cFVII transgene. Sustained and supraphysiological expression of 770% normal was observed using 4.95E13 vg/kg of AAV (2.6 years, ongoing). No evidence of pathological activation of coagulation or detrimental animal physiology was observed as platelet counts, d-dimer, fibrinogen levels, and serum chemistries remained normal in all dogs (cumulative 6.4 years). We observed a transient and noninhibitory immunoglobulin G class 2 response against cFVII only in the dog receiving the highest AAV dose. In conclusion, in the only large-animal model representing the majority of FVII mutation types, our data are first to demonstrate the feasibility, safety, and long-term duration of AAV-mediated correction of FVII deficiency.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Factor VII Deficiency
Genetic enhancement
Genetic Vectors
Immunology
Gene Expression
030204 cardiovascular system & hematology
Biology
Biochemistry
Immunoglobulin G
Adenoviridae
03 medical and health sciences
chemistry.chemical_compound
Dogs
0302 clinical medicine
hemic and lymphatic diseases
Zymogen
Internal medicine
medicine
Animals
Humans
Point Mutation
Missense mutation
Platelet
Transgenes
cardiovascular diseases
Protein Precursors
Factor VII
Genetic Therapy
Gene Therapy
Cell Biology
Hematology
HEK293 Cells
030104 developmental biology
Endocrinology
Coagulation
chemistry
Hemostasis
biology.protein
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 127
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....626919b0ac28fc8515222abac7d8f427