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AAV shedding after intracoronary delivery: just a safety concern?

Gene Therapy volume 27, pages 111–112 (2020)Cite this article

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Adeno-associated virus (AAV) offers several advantages over other vectors for treating heart failure using gene therapy. These advantages include the ability to transduce cardiomyocytes efficiently relative to nonviral vectors, long-term transgene expression, minimal immune response to the vector, and no integration of therapeutic genes into the patient genome [1]. Although AAV serotype 9 has been shown to achieve efficient cardiac gene transduction in rodents after tail vein injection, peripheral venous injection appears to achieve little cardiac gene transduction, if any, in more advanced mammals. In order to transduce the heart using safe and realistic amounts of AAV vectors in large animals and humans, specific cardiac targeting is necessary. Catheter-based intracoronary delivery is the most suitable method for cardiac targeting in patients with heart failure, because it is less invasive compared with other delivery methods that require open-thorax surgeries. In addition, the catheters for injection are readily available in clinical catheterization suites with established techniques. Indeed, intracoronary delivery was the method of choice for the first AAV-based cardiac gene therapy clinical trial, which delivered 1.0 × 1013 DNase-resistant particles of AAV1 encoding sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Unfortunately, the study failed to meet the primary efficacy endpoint in the phase 2b trial [2]. Meanwhile, both the phase 1/2a and 2b trials [2, 3] reported no obvious safety concerns associated with intracoronary AAV gene therapy, supporting the safety profile of AAV gene therapy for patients.

What has not been reported, however, is the safety of the treatment for people around the patient. Unlike chemically synthesized molecules, AAV is a biological vector that could in theory replicate with the aid of a helper virus in a suitable environment. Therefore, AAV particles shed from a patient’s body could replicate if conditions for the vectors are optimal. To our knowledge, functionality of virus shedding has not been intensively studied in the AAV1.SERCA2a trial. This was likely because the trial followed the Food and Drug Administration guidance for designing shedding studies in gene therapy [4]. In this guidance, qPCR was the recommended method for evaluating the shedding of replication incompetent products, such as AAV. It is rational for the trial to follow this guidance, since existing data in past trials using intradermal or intravenous AAV delivery exhibited low vector shedding; the dose used in the AAV1.SERCA2a trial was lower than in many previous trials; it was considered unlikely that the environment for excreta would offer an optimal setting for AAV to replicate; and AAV1.SERCA2a has not been shown to induce any diseases. Nonetheless, a lack of data on shedding does not validate that shed AAV is harmless in the patient’s environment.

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  1. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kelly P. Yamada, Taro Kariya & Kiyotake Ishikawa

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  1. Kelly P. Yamada
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Correspondence to Kiyotake Ishikawa.

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Yamada, K.P., Kariya, T. & Ishikawa, K. AAV shedding after intracoronary delivery: just a safety concern?. Gene Ther 27, 111–112 (2020). https://doi.org/10.1038/s41434-019-0115-2

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