Deborah Hursh, Ph.D. Office of Cellular, Tissue, and Gene Therapies

1. Mitochondrial Manipulation Technology in Assisted Reproduction For the Prevention of Transmission of Mitochondrial Disease or Treatment of Infertility Deborah Hursh, Ph.D. Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research Cellular, Tissue, and Gene Therapies Advisory Committee Meeting Feb. 25-26, 2014

2. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting # 59, Feb.25-26, 2014 • Feb. 25-26: Mitochondrial Manipulation Technology in Assisted Reproduction For The Prevention of Transmission of Mitochondrial Disease or Treatment of Infertility • Feb. 26: Considerations For The Design of Early-phase Clinical Trials of Cellular And Gene Therapy Products

3. FDA Oversight • FDA regulates human cells and tissues, including reproductive tissues, intended for transfer into humans under Section 361 of the Public Health Service Act • Focus on communicable disease • FDA regulates cell and gene therapies under Section 351 of the Public Health Service Act and the Food, Drug and Cosmetic Act • Premarket Approval, Safety and Effectiveness • Requirement for Investigational New Drug (IND) application

4. FDA Oversight • 2001: Letter to Sponsors/Researchers on Human Cells Used in Therapy Involving the Transfer of Genetic Material by Means Other than the Union of Gamete Nuclei • Response to published reports of ooplasm transfer • May 2002- FDA advisory committee meeting on Ooplasm Transfer in Assisted Reproduction • Identified unresolved safety questions

5. Purpose of the Meeting • Discuss potential future clinical trials of mitochondrial manipulation technologies • To prevent transmission of mitochondrial disease from affected women to their children • For the treatment of female infertility • Not intended to focus on a specific mitochondrial manipulation technology • No specific clinical trial is being discussed • Not intended to support any specific regulatory action, although the discussion may inform potential future regulatory deliberations

6. Scope of Meeting • FDA’s delegated authority is the protection of human subjects • Mitochondrial manipulation technologies may cause heritable genetic modifications • The ethical, legal, and social policy issues raised by heritable genetic modification are outside FDA’s delegated authority and will not be a topic of this meeting

7. Mitochondria: Energy-Producing Subcellular Organelles • Production of energy (ATP) by oxidative phosphorylation • Production of reactive oxygen species (ROS) • Regulation of calcium homeostasis • Programmed cell death (apoptosis)

8. Mitochondria Contain Their Own Genome • Small, ~ 17 kb • 37 genes • Many copies per cell • Inherited maternally • High mutation rate • Mutations cause human disease

9. Mitochondrial Manipulation Technology • Assisted reproduction technologies intended to modify the mitochondrial population of an oocyte or zygote • Reconstitute the maternal mitochondrial population to prevent transmission of mitochondrial disease from an affected woman to her children, or to treat female infertility • Supplement the mitochondrial composition of an oocyte to treat female infertility

10. Maternal Spindle Transfer Pronuclear Transfer

11. Mitochondrial Transfer

12. Discussion Topic 1 The goal of mitochondrial manipulation technologies is the prevention of transmission of mitochondrial disease from an affected woman to her children or the treatment of infertility. Prior to human clinical investigations, animal and in vitro studies provide the primary data upon which safety assessment is made. In the context of the available animal models or other experimental systems for mitochondrial manipulation technologies, please consider the specific objectives of studies that would be necessary to support the safety and prospect of benefit of mitochondrial manipulation technologies prior to first-in-human clinical trials. Please discuss the ability of available animal models and/or in vitro methods to address the following: • The possibility of inadvertent damage to the manipulated oocyte or embryo. • The long-term risks associated with the carryover of abnormal mtDNA and heteroplasmy in the children. • The potential for abnormal embryo/fetal growth, resulting in children with significant defects.

13. Discussion Topic 2 • Please discuss the potential risks of mitochondrial manipulation technologies to the women with either mitochondrial disease or infertility, and to the resulting children.

14. Discussion Topic 3 Please discuss the following elements of the design of first-in-human trials to assess the safety and efficacy of mitochondrial manipulation technologies to prevent mitochondrial diseases in children of affected women, and to treat female infertility: • Major enrollment criteria. For example, for trials to prevent transmission of mitochondrial diseases, eligibility criteria might limit enrollment to women with specific mtDNA mutations, clinical manifestations, disease severity, extent of heteroplasmy, or other factors. Selection of only male embryos for transfer might be an option to minimize the risk of transmitting mitochondrial disease to subsequent generations. • For trials to treat infertility, some types of assessments of mitochondrial number or function might be useful in screening women with infertility for enrollment.

15. Discussion Topic 3, cont. • The controls (comparators), either concurrent or historical, that should be included in trials to provide evidence of safety and efficacy. • Procedures to monitor safety and efficacy during fetal development, in the perinatal period, during early childhood, and thereafter. In addition, for trials to prevent transmission of mitochondrial diseases, female children, but not male children, could transmit a mitochondrial disease to future generations; safety monitoring could be extended to subsequent generations of female children. • Any measures (including, but not limited to, assent or informed consent of the children) that might be necessary for the ethical conduct of long-term follow-up of the children, and subsequent generations of any female children. • Measurements of efficacy.

16. Discussion Topic 4 Adequate manufacturing controls and monitoring of processes are essential to protect the safety of subjects and to minimize the risks for any children that might result from clinical trials using mitochondrial manipulation technologies. Noting that the specific controls might differ for each process, please discuss controls for and/or methods for assessing the following: • The source and characteristics of the mitochondria or other subcellular materials. Examples might include tests of mtDNA or spindle integrity, quantitation of mitochondria for transfer, and methods to measure the success of nuclear genome or mitochondrial transfer. • The source of the oocytes or other cells. • The reagents used in mitochondrial manipulation technologies (e.g., colchicine; Sendai virus extract). • The method(s) for qualifying manipulated embryos prior to transfer, including any genetic tests.

17. Gerald S. Shadel, Ph.D. Director, Pathology Research, Departments of Pathology and Genetics, Yale School of Medicine Salvatore DiMauro, M.D., Professor of Neurology College of Physicians & Surgeons, Columbia University Medical Center Marc-André Sirard, D.M.V., Ph.D., Chaire de Recherche du Canada en Génomique Animale Département des Sciences Animales Pavillon des services, Université Laval Keith Latham, Ph.D., Professor of Animal Science College of Agriculture and Natural Resources Michigan State University Invited Speakers

18. Invited Speakers Shoukhrat Mitalipov, Ph.D., Senior Scientist Oregon National Primate Research Center Oregon Health & Science University Dieter Egli, Ph.D., Senior Research Fellow The New York Stem Cell Foundation Mary Herbert, Ph.D., Professor of Reproductive Biology Institute for Aging and Health, Newcastle University

19. Deborah Hursh Malcolm Moos Wei Liang Lei Xu Bruce Schneider Kimberly Benton Raj Puri Mercedes Serabian Ilan Irony Wilson Bryan Samuel Barone Gail Dapolito Rachael Anatol Richard McFarland Cheryl Giganti Stephanie Simek Celia Witten Shelley Slaughter Rhonda Stokes-Hearns Sara Goldkind Michelle Roth-Cline Robert Nelson Fa-ry Grant Brian Stultz Susan Roman Planning Committee