CERSI-FDA Workshop on Prenatal Somatic Cell Gene Therapies

Tuesday, October 26, 2021
7 AM – 2 PM Pacific Time
(10 AM – 5 PM Eastern Time

Virtual Workshop – Meeting will be held over Zoom

Meeting proceedings published in the Journal of Clinical Pharmacology in September 2022 (PMID 36106778)

UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI)

The first regulatory science and innovation center on the West Coast

Prenatal Somatic Cell Gene Therapies: Charting a Path Forward for Clinical Applications

Overview

As gene therapy gains momentum in treating single gene disorders in pediatric and adult patients, it is an apt time to discuss clinical applications to treat fetuses with severe or fatal genetic diseases. Preclinical data underscore the possible advantages of gene therapy or gene editing before birth: fetal exposure to a missing protein may result in tolerance; treating before formation of the blood-brain barrier may improve neurologic function; and early treatment may improve survival for many progressive diseases, some of which are fatal before birth. There are also risks and other considerations that are particular to prenatal application. We are convening a group of scientists, clinicians, ethicists, patient advocates, and regulatory professionals to assess the risks and benefits of prenatal somatic cell gene therapy (PSCGT) in humans. Discussion will focus on therapies that target somatic cells of fetuses with severe, early onset disorders.

The objective of the virtual workshop is to consider the various scientific, clinical, ethical, and regulatory aspects of prenatal somatic cell gene therapy for fetuses with severe, early onset genetic diseases and to articulate a prudent roadmap for first-in-human clinical applications.

The workshop will:

• Summarize the current state of fetal therapy, including the path to IND for current prenatal medical therapies (stem cell and enzyme replacement therapy).
• Consider the available preclinical data and scientific rationale for prenatal gene therapy in various animal models.
• Review several gene therapy and gene editing strategies currently in clinical trials for postnatal indications, using spinal muscular atrophy as an example.
• Examine principles of fetal and maternal monitoring, informed consent, and patient perspectives in designing a clinical trial.

This virtual collaborative workshop is co-sponsored by the UCSF-Stanford CERSI, the UCSF Center for Maternal-Fetal Precision Medicine, and the U.S. Food and Drug Administration.

Recordings

Welcome Session

Session 1

Session 2

Session 3

Session 4

Agenda

Please click here to download the  Speaker Biographies.

Time (PT)	Topic	Speaker
7:00 am	Introduction and Welcome	Tippi MacKenzie, MD University of California San Francisco
7:05 am	Patient Story: Experience with Prenatal Diagnosis of Severe Genetic Disease	Billie Lianoglou, LCGC, MS University of California San Francisco
	SESSION 1: Background on Fetal Diagnosis and Therapy
7:20 am	Overview of Fetal Therapy TodayWe will review the current state of fetal therapies offered for anatomic disorders, the evolution to treat severe diseases that are not lethal in utero and evolving medical therapies such as stem cell transplantation and protein replacement.	Tippi MacKenzie, MD University of California San Francisco
7:40 am	Relevant Diseases for Prenatal Gene TherapyWe will review the genetics of disorders that are amenable to prenatal gene therapy (including considerations for genotype/phenotype correlations, severity, and age of onset) and biomarkers to monitor efficacy.	Stephan Sanders, BMBS, PhD University of California San Francisco
8:00 am	Prenatal DiagnosisWe will review the state of prenatal diagnosis for anatomic and genetic diseases, including considerations for identifying genetic disorders that do not have obvious ultrasound manifestations.	Teresa Sparks, MD University of California San Francisco
8:20 am	Q & A
8:30 am	BREAK
	SESSION 2: Preclinical Data for Prenatal Gene Therapy in Specific Diseases
8:40 am	MPS1 and Monogenic Lung DiseaseWe will review preclinical data regarding safety and efficacy of CRISPR gene editing in utero to treat mice with MPS 1, as well as data for targeting the fetal lung in a mouse model of surfactant protein deficiency.	William Peranteau, MD Children’s Hospital of Philadelphia
8:55 am	Beta Thalassemia and Cystic FibrosisWe will review data demonstrating the ability to target fetal hematopoietic stem cells using gene editing to treat beta thalassemia in mice. We will also review data on targeting the developing fetal lung to treat CFTR mutation.	David Stitelman, MD Yale University
9:10 am	HemophiliaWe will review preclinical data from studies of prenatal gene therapy (in mouse, sheep, and non-human primates) to express a clotting factor, as well as evidence of tolerance induction to an exogenous protein after in utero exposure.	Graça Almeida-Porada, MD, PhD Wake Forest
9:30 am	Overview of Available Data on Germline TransductionWe will review experiments quantifying exposure to viral vectors after prenatal gene therapy in the sheep model.	Christopher Porada, PhD Wake Forest
9:45 am	Panel DiscussionWe will discuss how the available preclinical data relate to potential regulatory applications for prenatal gene therapy, as well as remaining scientific gaps to improve safety and efficacy.Panelists:    Graça Almeida-Porada, MD, PhD – Wake Forest   Lois Freed, PhD – U.S. Food and Drug Administration   William Peranteau, MD –  Children’s Hospital of Philadelphia   Christopher Porada, PhD – Wake Forest   David Stitelman, MD – Yale University	ModeratorAgnieszka Czechowicz, MD, PhD Stanford University
10:15 am	BREAK
	SESSION 3: Considerations for Clinical Translation
10:40 am	Ethical Consideration for Prenatal Gene TherapyWe will discuss considerations for performing clinical trials during pregnancy, as well as considerations for avoiding germline editing in any setting.	R. Alta Charo, JD University of Wisconsin at Madison
11:00 am	Case Scenario for Prenatal Gene Therapy: Spinal Muscular AtrophyWe will consider SMA as an example to understand the necessary IND-enabling studies to assess the safety and efficacy of available therapeutics that could be administered prenatally. We will review the scientific rationale for early treatment and available data for using either antisense oligonucleotides or aav gene therapy.	Charlotte Sumner, MD Johns Hopkins University
11:30 am	Preclinical Considerations for Gene Therapy Products: An FDA PerspectiveThis presentation will provide an overview of the preclinical testing program to inform clinical development for gene therapy products.	Ying Huang, PhD U.S. Food and Drug Administration
12:00 pm	Procedural Considerations for Delivery of Prenatal Therapies: IntravascularWe will review the safety profile of fetal umbilical vein injections, performed commonly for intrauterine transfusions.	Juan Gonzalez Velez, MD, PhD University of California San Francisco
12:10 pm	Procedural Considerations for Delivery of Prenatal Therapies: IntracerebroventricularWe will review considerations for delivery of therapeutics into the fetal cerebrospinal fluid, such as the feasibility of intraventricular injections.	Nalin Gupta, MD, PhD University of California San Francisco
12:20 pm	Maternal and Fetal Safety ConsiderationsWe will review safety considerations of prenatal gene therapy for the mother and the fetus, including protocols to detect potential adverse events during and after pregnancy.	Anna David, MB ChB, PhD University College London
12:40 pm	Q & A
12:55 pm	BREAK
	SESSION 4: Balancing Safety and Innovation
1:05 pm	Mila’s Path to Truly Personalized Medicine
1:15 pm	Panel DiscussionWe will discuss the balance between developing life-saving therapies while ensuring safety of clinical trial participants.Panelists:    P.J. Brooks, PhD – National Center for Advancing Translational Sciences   Barbara Koenig, PhD – University of California San Francisco   Kevin Prohaska, DO, MPH – U.S. Food and Drug Administration   Fyodor Urnov, PhD – University of California, Berkeley   Julia Vitarello – Mila’s Miracle Foundation	ModeratorTippi MacKenzie, MD University of California San Francisco
1:55 pm	Closing RemarksTippi MacKenzie, MD – University of California San Francisco	Tippi MacKenzie, MD University of California San Francisco
2:00 pm	Adjournment

Workshop Planning Committee

We thank the following members of the workshop planning committee for their time and expertise:

• Tippi MacKenzie, MD – Chair
• Graça Almeida-Porada, MD, PhD
• Larissa Lapteva, MD
• Lawrence Lin, PhD
• William Peranteau, MD
• Christopher Porada, PhD
• David Stitelman MD
• Evi Struble, PhD
• Members of the UCSF Center for Maternal-Fetal Precision Medicine