Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B.

Adeno-associated virus (AAV) vectors are a leading platform for gene-based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer outstanding clinical questions of safety, durability, and the nature of the human immune response to AAV vectors. Here, we present longitudinal follow-up data of subjects who participated in the first trial of a systemically delivered AAV vector. Adult males (n = 7) with severe hemophilia B received an AAV2 vector at doses ranging from 8 × 1010 to 2 × 1012 vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n = 4) was followed for 12-15 years post-vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum α-fetoprotein, and liver ultrasound. Subjects demonstrated persistent, increased AAV neutralizing antibodies (NAbs) to the infused AAV serotype 2 (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow-up. These data represent the longest available longitudinal follow-up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAbs for up to 15 years post- AAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy.

George LA ，Ragni MV ，Rasko JEJ ，Raffini LJ ，Samelson-Jones BJ ，Ozelo M ，Hazbon M ，Runowski AR ，Wellman JA ，Wachtel K ，Chen Y ，Anguela XM ，Kuranda K ，Mingozzi F ，High KA ... -  《-》

Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial.

Monahan PE ，Sun J ，Gui T ，Hu G ，Hannah WB ，Wichlan DG ，Wu Z ，Grieger JC ，Li C ，Suwanmanee T ，Stafford DW ，Booth CJ ，Samulski JJ ，Kafri T ，McPhee SW ，Samulski RJ ... -  《-》

Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice.

Scallan CD ，Jiang H ，Liu T ，Patarroyo-White S ，Sommer JM ，Zhou S ，Couto LB ，Pierce GF ... -  《BLOOD》

Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes.

Li H ，Murphy SL ，Giles-Davis W ，Edmonson S ，Xiang Z ，Li Y ，Lasaro MO ，High KA ，Ertl HC ... -  《MOLECULAR THERAPY》

Targeted modifications in adeno-associated virus serotype 8 capsid improves its hepatic gene transfer efficiency in vivo.

Sen D ，Gadkari RA ，Sudha G ，Gabriel N ，Kumar YS ，Selot R ，Samuel R ，Rajalingam S ，Ramya V ，Nair SC ，Srinivasan N ，Srivastava A ，Jayandharan GR ... -  《-》