Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting)

Akos Herzeg^{1

2

3}, Graça Almeida-Porada^{4

5}, R Alta Charo⁶, Anna L David^{7

8}, Juan Gonzalez-Velez^{1

9}, Nalin Gupta^{10

11

12}, Larissa Lapteva¹³, Billie Lianoglou^{1

2}, William Peranteau¹⁴, Christopher Porada^{4

5}, Stephan J Sanders^{1

15

16

17}, Teresa N Sparks^{1

9}, David H Stitelman¹⁸, Evi Struble¹³, Charlotte J Sumner¹⁹, Tippi C MacKenzie^{1

2

9

12}

Affiliations

¹ UCSF Center for Maternal-Fetal Precision, Medicine, San Francisco, California, USA.
² Department of Surgery, University of California, San Francisco, California, USA.
³ Department of Obstetrics and Gynecology, Goethe University Frankfurt, Frankfurt am Main, Germany.
⁴ Fetal Research and Therapy Program, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston Salem, North Carolina, USA.
⁵ Wake Forest University, School of Medicine, Winston-Salem, North Carolina, USA.
⁶ University of Wisconsin Law School, Madison, Wisconsin, USA.
⁷ Elizabeth Garrett Anderson Institute for Women's Health, University College London Medical School, London, UK.
⁸ National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK.
⁹ Department of Obstetrics and Gynecology, University of California, San Francisco, California, USA.
¹⁰ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
¹¹ Brain Tumor Center, University of California San Francisco, San Francisco, California, USA.
¹² Department of Pediatrics and Benioff Children's Hospital, University of California San Francisco, San Francisco, California, USA.
¹³ Office of Tissues and Advanced Therapies/Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Washington, DC, USA.
¹⁴ Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
¹⁶ Institute for Human Genetics, University of California, San Francisco, California, USA.
¹⁷ Bakar Computational Health Sciences Institute, University of California, San Francisco, California, USA.
¹⁸ Yale University School of Medicine, Department of Surgery, Division of Pediatric Surgery, New Haven, CT, USA.
¹⁹ Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 36106778
PMCID: PMC9547535
DOI: 10.1002/jcph.2127

Review

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting)

Akos Herzeg et al. J Clin Pharmacol. 2022 Sep.

. 2022 Sep;62 Suppl 1(Suppl 1):S36-S52.

doi: 10.1002/jcph.2127.

Authors

Affiliations

¹ UCSF Center for Maternal-Fetal Precision, Medicine, San Francisco, California, USA.
² Department of Surgery, University of California, San Francisco, California, USA.
³ Department of Obstetrics and Gynecology, Goethe University Frankfurt, Frankfurt am Main, Germany.
⁴ Fetal Research and Therapy Program, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston Salem, North Carolina, USA.
⁵ Wake Forest University, School of Medicine, Winston-Salem, North Carolina, USA.
⁶ University of Wisconsin Law School, Madison, Wisconsin, USA.
⁷ Elizabeth Garrett Anderson Institute for Women's Health, University College London Medical School, London, UK.
⁸ National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK.
⁹ Department of Obstetrics and Gynecology, University of California, San Francisco, California, USA.
¹⁰ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
¹¹ Brain Tumor Center, University of California San Francisco, San Francisco, California, USA.
¹² Department of Pediatrics and Benioff Children's Hospital, University of California San Francisco, San Francisco, California, USA.
¹³ Office of Tissues and Advanced Therapies/Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Washington, DC, USA.
¹⁴ Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
¹⁶ Institute for Human Genetics, University of California, San Francisco, California, USA.
¹⁷ Bakar Computational Health Sciences Institute, University of California, San Francisco, California, USA.
¹⁸ Yale University School of Medicine, Department of Surgery, Division of Pediatric Surgery, New Haven, CT, USA.
¹⁹ Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 36106778
PMCID: PMC9547535
DOI: 10.1002/jcph.2127

Abstract

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

Keywords: drug development; fetal medicine; immunopharmacology; neurology; pediatrics; perinatology; pharmacogenetics/pharmacogenomics; rare diseases; regulatory/scientific affairs; women's health.

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Conflict of interest statement

Conflicts of Interest

Anna L. David is the co-chair of the Maternal Health Project Group of ABPI and the Association of British Pharmaceutical Industry (unpaid position), and consults for Esperare Foundation, Geneva, Switzerland, a private not-for-profit developing a prenatal therapy for a congenital skin disease. Stephan J. Sanders receives research funding from BioMarin Pharmaceutical Inc. Charlotte J. Sumner has been a consultant to Avexis, Novartis, Ionis Pharmaceuticals, Biogen, PTC Therapeutics, Roche, Genentech, Cytokinetics, Sarepta, Nura Bio, Argenx, Biomarin, Scholar Rock, GenEdit, Epirium, Capsigen, and Atalanta. She received research grants from Ionis Pharmaceuticals and Argenx, and currently receives grant support from Roche. She is a coholder of two pending patent applications (BIOL0274USA and BIOL0293WO) with Ionis Pharmaceuticals on antisense oligonucleotides targeting SMN-AS1. She receives royalties from Elsevier for the book Spinal Muscular Atrophy: Disease Mechanisms and Therapy (editors, C.J. Sumner, S. Paushkin, C.P. Ko; Elsevier, 2017). Tippi C. MacKenzie current or past research funding from Novartis, BioMarin, and Ultragenyx. She is a member of the Scientific Advisory Board of Acrigen (gene editing company). Larissa Lapteva and Evi Strubble: no conflicts of interest. The opinions presented in this article are those of the authors and do not necessarily represent the views or policies of the Food and Drug Administration. Nalin Gupta is the consultant for Encoded Therapeutics and Sana Therapeutics.

References

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Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting)

Affiliations

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting)

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical