Abstract
Adeno-associated virus (AAV) vectors represent promising candidates for gene therapy; however, pre-existing neutralizing antibodies (NAb) may reduce AAV vector delivery efficiency. In this study, the presence of AAV NAb was investigated in cats, which serve as a larger and outbred animal model for the prediction of gene therapy outcomes in humans but also in cats.Serum/plasma samples from 230 client-owned Swiss cats and 20 specified pathogen-free cats were investigated for NAb to AAV1, AAV2, AAV5, AAV6, AAV7, AAV8 and AAV9 using in vitro transduction inhibition and a beta-galactosidase assay. NAb to all tested AAV serotypes were found. Of the client-owned cats, 53% had NAb to one or more of the AAV serotypes. NAb (≥1:10) were found at frequencies of 5% (AAV6) to 28% (AAV7). The highest titers were found against AAV7 (≥1:160). The NAb prevalence to AAV2, AAV7 and AAV9 differed geographically. Regarding titers ≥1:10 against single AAV serotypes, age, breed and sex of the cats were not associated with the NAb prevalence. Cats with titers ≥1:20 against AAV2 and titers ≥1:40 against AAV7 were significantly younger than cats with low/no titers, and purebred cats were significantly more likely than non-purebred cats to have NAb to AAV2 (≥1:40). Additionally, regarding NAb to all AAV combined, female cats were significantly more likely than male cats to have NAb titers ≥1:40. Preliminary data using AAV-DJ indicated that less pre-existing NAb to the hybrid AAV-DJ can be expected compared to the wild-type AAV serotypes. AAV NAb will need to be taken into account for future in vivo gene therapy studies in cats.
Highlights
Treatment of many genetic and acquired diseases remains a challenge
Samples from the 230 client-owned cats and 20 specified pathogen-free (SPF) cats were analyzed for the presence of neutralizing antibodies (NAb) against AAV1, AAV2, AAV5, AAV6, AAV7, AAV8 and AAV9
NAb titers from all client-owned cats are summarized in Fig 1; the geographic origin of the samples with NAb is depicted in Fig 2 and listed in S1 and S2 Tables categorized into the different cantons and regions
Summary
Treatment of many genetic and acquired diseases remains a challenge. New classes of therapeutics are being developed; these development efforts include the investigation and application of gene therapy. AAV has been used as a vector for over 20 years [4] in more than 100 clinical trials. Several of these trials show great promise, such as gene therapy for hemophilia B [5, 6], Leber’s congenital amaurosis [7, 8] and Parkinson’s disease [9]. Few AAV-vector-mediated gene therapies have already been approved in Europe including Alipogene Tiparvovec, a treatment of lipoprotein lipase deficiency as well as Luxturna a one-time gene therapy for the treatment of an inherited retinal dystrophy [10, 11]
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