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.

Regulation of NGF Signaling by an Axonal Untranslated mRNA.

Neurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner.

Academic Productivity of Interventional Pulmonology Training Programs.

RATIONALE: The Hirsch index (h-index) has been validated as a measure of academic productivity and may be an appropriate tool to assess the scholarly activity of interventional pulmonology (IP). OBJECTIVES: This study aimed to elucidate the factors associated with increasing h-index scores among IP training programs. METHODS: A cross-sectional study was conducted of IP training programs across the United States and Canada. Data, including their respective h-index, number of publications, academic rank, geographic location, and possession of an advanced degree, were collected on IP faculty and fellows from 23 teaching institutions. MEASUREMENTS AND MAIN RESULTS: Ninety-three IP physicians (48 faculty, 45 fellows) in all were included in the study from 23 institutions with a total of 101 data points. The faculty h-index mean was 3.88. The proportion of faculty with an h-index greater than the mean value was increased significantly with higher academic rank (P < 0.0001). In addition, physicians holding an advanced degree beyond an M.D./D.O. had a significantly higher h-index than did those without (P = 0.0062). CONCLUSIONS: For academic interventional pulmonologists, the h-index rises with increasing academic rank and possession of an advanced degree. The h-index for IP is roughly comparable to that for other surgical and procedural-based specialties.