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 , 2014

2. Cellular, Tissue, and Gene Therapies Advisory Committee Meeting # 59, Feb.25-26, 2014
Feb : 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 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. Invited Speakers
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

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. Planning Committee Rachael Anatol Deborah Hursh 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
Deborah Hursh
Malcolm Moos
Wei Liang
Lei Xu
Bruce Schneider
Kimberly Benton
Raj Puri
Mercedes Serabian
Ilan Irony
Wilson Bryan
Samuel Barone
Gail Dapolito