Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype

Abstract

Despite the popularity of adeno-associated virus 2 (AAV2) as a vehicle for gene transfer, its efficacy for liver-directed gene therapy in hemophilia A or B has been suboptimal. Here we evaluated AAV serotypes 2, 5, 7, and 8 in gene therapy of factor VIII (FVIII) deficiency in a hemophilia A mouse model and found that AAV8 was superior to the other 3 serotypes. We expressed canine B domain-deleted FVIII cDNA either in a single vector or in 2 separate AAV vectors containing the heavy- and light-chain cDNAs. We also evaluated AAV8 against AAV2 in intraportal and tail vein injections. AAV8 gave 100% correction of plasma FVIII activity irrespective of the vector type or route of administration.

Immune responses to gene therapy vectors: influence on vector function and effector mechanisms

“…54 AAV-8, which has been used recently for gene therapy, is more efficient than AAV-2, -5, and -7 for infecting liver cells, and AAV-8 encoding FVIII is also more efficient in the treatment of hemophilia in mice. 55 Studies have shown that neutralizing antibodies to AAV-7 and AAV-8 are rare in human sera, 56 so that these serotypes are good candidate vectors for humans. Similarly, most humans have no neutralizing antibodies to the group B adenovirus serotype 35.…”

Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA

“…Among several recently isolated serotypes, AAV8 possesses high transduction rate in liver and low preexisting immunity in human population, therefore, is an attractive vector for liver gene delivery. [29][30][31][32][33] Another major advancement in AAV vector development was the discovery that AAV with self-complementary doublestranded genome possessed 10-to 100-fold higher transduction rate in liver than conventional singlestranded AAV. 34,35 We, therefore, decided to construct double-stranded AAV2/8 pseudotyped vector (dsAAV2/8) to deliver shRNAs and to investigate its inhibition effects in HBV transgenic mice.…”

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer

“…10 Preclinical experiments with AAV in animal models for different diseases have proven the long-term stable transgene expression in liver, muscle, and central nervous system. [11][12][13][14][15][16][17] Several early-phase clinical trials with AAV vectors have been initiated and shown to be safe. [18][19][20][21] Among the at least eight different AAV natural serotypes discovered so far, AAV vector derived from serotype 2 (AAV2) has been the most extensive studied and widely used AAV vector in the past 20 years.…”

“…27,28 However, route-independent, that is, tail-vein application, and long-term therapeutic effects in females were not achieved despite very high doses of rAAV vector administration (up to 10 14 viral particles per mouse). Since AAV serotype 2 and 5 have been shown to have a low efficiency in liver transduction, 12 alternative serotypes, as discussed above, might be employed for liverdirected gene transfer. Here, we show a long-term, administration-route and gender-independent therapeutic correction of PKU mice by hepatic gene transfer with a rAAV serotype 8 vector.…”