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Titolo:
Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation
Autore:
Herzog, RW; Mount, JD; Arruda, VR; High, KA; Lothrop, CD;
Indirizzi:
Auburn Univ, Coll Vet Med, Scott Ritchey Res Ctr, Auburn, AL 36849 USA Auburn Univ Auburn AL USA 36849 ott Ritchey Res Ctr, Auburn, AL 36849 USA Auburn Univ, Coll Vet Med, Dept Clin Sci, Auburn, AL 36849 USA Auburn Univ Auburn AL USA 36849 Med, Dept Clin Sci, Auburn, AL 36849 USA Univ Penn, Med Ctr, Dept Pediat, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 pt Pediat, Philadelphia, PA 19104 USA Univ Penn, Med Ctr, Dept Pathol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 pt Pathol, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia Philadelphia PA USA 19104 lphia, PA 19104 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 3, volume: 4, anno: 2001,
pagine: 192 - 200
SICI:
1525-0016(200109)4:3<192:MGTATI>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
COAGULATION-FACTOR-IX; ADENOASSOCIATED VIRUS; TERM CORRECTION; EXPRESSION; THERAPY; VECTOR; DOGS; INHIBITORS; TOLERANCE;
Keywords:
hemophilia B dogs; factor IX; AAV; gene transfer; muscle;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Lothrop, CD Auburn Univ, Coll Vet Med, Scott Ritchey Res Ctr, Auburn, AL 36849 USA Auburn Univ Auburn AL USA 36849 Res Ctr, Auburn, AL 36849 USA
Citazione:
R.W. Herzog et al., "Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation", MOL THER, 4(3), 2001, pp. 192-200

Abstract

The X-linked bleeding disorder hemophilia B is caused by absence of functional blood coagulation factor IX (F9) and can be treated by adeno-associated viral (AAV) mediated gene transfer to skeletal muscle. The safety of thisapproach is currently being evaluated in a phase I clinical trial. Efficacy of this and several other gene therapy strategies has been addressed in hemophilia B dogs, an important preclinical model of the disease. While previously published data demonstrated sustained expression of canine F9 in dogs with a missense mutation in the gene F9, we show here that AAV-mediated canine F9 gene transfer to skeletal muscle of hemophilia B dogs carrying a null mutation of F9 (causing an early stop codon and an unstable mRNA) results in induction of inhibitory anticanine F9 at comparable vector doses (1 x10(12) vector genomes/kg). Thus, the risk of inhibitor formation followingAAV-mediated F9 gene therapy may be influenced by the nature of the underlying mutation in F9. Transient immune suppression with cyclophosphamide at the time of vector administration blocked formation of anti-canine F9 antibodies in the one animal treated with this approach. Treatment with this combination of gene transfer and transient immune modulation has resulted in sustained expression (> 8 months) of canine F9 at levels sufficient for partial correction of coagulation parameters.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/02/20 alle ore 21:43:29