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Comment on: Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets

Gene Therapy volume 30, pages 232–235 (2023)Cite this article

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The Original Article was published on 22 November 2021

There has been great advancement in the field of gene therapy in recent years with over 700 active gene therapy investigational drugs currently being studied [1]. While postnatal use of these therapies is promising, in utero gene therapy (IUGT) and gene editing may allow correction of disease before the onset of irreversible pathology [2]. IUGT takes advantage of normal fetal ontogeny, including the small fetal size, tolerant fetal immune system, and access to privileged compartments and progenitor cell populations to overcome potential limitations to postnatal therapy [3]. In the article titled “Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets,” Rich et al. outline a set of pivotal experiments focused on using the fetal pig as a model for IUGT [4].

The majority of proof-of-concept IUGT studies have been performed in the rodent, which offers the advantages of small size, easy handling and mating, lower cost, multiparity, prevalence of multiple disease models, and an abundance of relevant biologic reagents to conduct studies. However, the translation of in utero therapies from the small animal model to the human is limited by distinct differences in embryology, development, and physiology [5]. While non-human primates (NHP) offer the greatest similarity to humans, they are limited by cost and availability, longer and usually single gestations, and ethical concerns [6]. Prior work in sheep has laid the foundation for some of the current knowledge of human development, maternal-fetal physiology, perinatal medicine, and in utero gene and cell therapies [7]. However, sheep have only 1–2 fetuses per pregnancy, limiting the analysis of multiple variables in one animal. The pig, in contrast, provides a large animal model with similarity to humans in terms of development, anatomy, pharmacology, genetics, and immunology, as well as a litter size of up to 14 fetuses (average: 7–8 fetuses/pregnancy), permitting short-term multivariate analyses in one animal [8]. In addition, there has been extensive research into the pig genome, which has been leveraged to perform CRISPR-Cas9 gene editing to create numerous pig models of human diseases as well as modify tissues for studies of xenotransplantation of pig organs [9, 10]. Therefore, pig models of human diseases may serve a critical role in the clinical translation of IUGT in the future.

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Fig. 1: Systemic AAV9.GFP delivery leads to successful GFP transduction in the pig fetal liver.
Fig. 2: Organ targeting and liver function following in utero systemic delivery of AAV9 in the fetal pig model.

Data availability

Data generated and analyzed during the current study are presented within the paper and are available from the corresponding author on reasonable request.

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Acknowledgements

We thank A.Weilerstein for his help with animal care.

Funding

This work was supported by grant DP2HL152427 (WHP) from the United States National Institute of Health (NIH) and generous family gifts to The Children’s Hospital of Philadelphia (CHOP) (WHP).

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Author notes

  1. These authors contributed equally: Apeksha Dave, Cara L Berkowitz.

Authors and Affiliations

  1. The Center for Fetal Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Apeksha Dave, Cara L. Berkowitz, Valerie L. Luks, Brandon M. White, Rohan Palanki, Marco D. Carpenter, John S. Riley, Sourav K. Bose, Haiying Li, Pallavi V. Menon, Shiva Teerdhala, Mina Ebrahimi, Philip W. Zoltick & William H. Peranteau

  2. Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Li Li

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Contributions

AD, CB, and WHP drafted the original paper and all authors subsequently revised it. All authors conducted the experiments and acquired data. AD, CB, MDC, PWZ, and WHP analyzed the data and interpreted the results of the experiments. WHP designed the study and oversaw its execution. All authors approved the final version and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to William H. Peranteau.

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Dave, A., Berkowitz, C.L., Luks, V.L. et al. Comment on: Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets. Gene Ther 30, 232–235 (2023). https://doi.org/10.1038/s41434-023-00395-0

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