Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy.
Hemophilia B, also known as Christmas disease, arises from mutations in the factor IX (F9) gene. Its treatment in humans, by recombinant protein substitution, is expensive, thus limiting its application to intermittent treatment in bleeding episodes and prophylaxis during surgery; development of inhibitory antibodies is an associated hazard. This study demonstrates permanent therapeutic correction of his disease without development of immune reactions by introduction of an HIV-based lentiviral vector encoding the human factor IX protein into the fetal circulation of immunocompetent hemophiliac and normal outbred mice. Plasma factor IX antigen remained at around 9%, 13%, and 16% of normal in the 3 hemophilia B mice, respectively, until the last measurement at 14 months. Substantial improvement in blood coagulability as measured by coagulation assay was seen in all 3 mice and they rapidly stopped bleeding after venipuncture. No humoral or cellular immunity against the protein, elevation of serum liver enzymes, or vector spread to the germline or maternal circulation were detected.
Waddington
Simon N
SN
Imperial College London, Gene Therapy Research Group, Section of Cell and Molecular Biology, Sir Alexander Fleming Bldg, Imperial College Road, London, SW7 2AZ, United Kingdom. s.waddington@imperial.ac.uk
Nivsarkar
Megha S
MS
Mistry
Ajay R
AR
Buckley
Suzanne M K
SM
Kemball-Cook
Geoffrey
G
Mosley
Karen L
KL
Mitrophanous
Kyriacos
K
Radcliffe
Pippa
P
Holder
Maxine V
MV
Brittan
Mairi
M
Georgiadis
Anastasios
A
Al-Allaf
Faisal
F
Bigger
Brian W
BW
Gregory
Lisa G
LG
Cook
H Terence
HT
Ali
Robin R
RR
Thrasher
Adrian
A
Tuddenham
Edward G D
EG
Themis
Mike
M
Coutelle
Charles
C
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D005164:Factor IX / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D005260:Female; D046128:Fetal Therapies / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007121:Immunocompetence; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D021041:Placental Circulation; D011247:Pregnancy
D005164:Factor IX