Here’s How The FDA Developed Rules For Therapeutic Cloning and Genome Modification

The rapid advances over the past few decades in biotechnologies involving somatic cells and gene therapy offer a great potential in regenerative medicine and for the treatment of genetic defects. These advances require an understanding of scientific principles as well as ethical and societal implications before these technologies can be clinically applicable.

Somatic Nuclear Transfer (SCNT) was successfully used in 1997 to create the cloned sheep Dolly. SCNT is a technique were the nucleus of a donor egg (oocyte) is removed and discarded and replaced with the nucleus from an adult somatic cell (i.e. skin cells, fat cells and liver cells). The egg is stimulated to divide into a blastocyst (early embryo with no more than about 100 cells) that has an identical genetic make-up to the original donor nuclear DNA (a clone). One attraction of SCNT is the resulting pluripotent cells would have the same genetic make-up as the patient’s, since the transplanted nucleus carries the patient’s DNA. SCNT does not involve reproduction since sperm is not used in the technique and therefore provides an alternative method of obtaining stem cells to be used in therapy or in research.

Embryonic stem cells (ESC) are undifferentiated cells from an embryo and have the ability to give rise to all of the tissues found the body. There is ethical and societal controversy surrounding the production of ESCs because production requires the destruction of viable human embryos.

On March 7, 1997 then President Clinton issued a memorandum that stated: “Recent accounts of advances in cloning technology, including the first successful cloning of an adult sheep, raise important questions. They potentially represent enormous scientific breakthroughs that could offer benefits in such areas as medicine and agriculture. But the new technology also raises profound ethical issues, particularly with respect to its possible use to clone humans.” (Prohibitions on Federal Funding for Cloning of Human Beings).

The memorandum explicitly prohibited Federal Funding for cloning of a human being, and also directed the National Bioethics Advisory Commission (NBAC) to thoroughly review the legal and ethical issues associated with the use of cloning technology to create a human being.
“NBAC found that concerns relating to the potential psychological harms to children and effects on the moral, religious, and cultural values of society merited further reflection and deliberation.” The report, Ethical Issues in Human Stem Cell Research, September 1999, describes 5 recommendations.

In March 2001, FDA sent a letter to the research community asserting regulatory authority over clinical research using cloning technology to create a human being, and to advise that FDA regulatory process is required in order to initiate these investigations. FDA jurisdiction includes human cells used in therapy involving the transfer of genetic material by means other than the union of gamete nuclei. Examples of such genetic material include, but are not limited to: cell nuclei (for cloning), oocyte nuclei, ooplasm, which contains mitochondria and genetic material contained in a genetic vector, transferred to gametes or other cells. Any clinical research involving these techniques would require an IND.

In the United States, SCNT remains legal, as it has not been addressed by federal law. However, in 2002, a moratorium on United States federal funding for SCNT prohibits funding the practice for the purposes of research. Thus, though legal, SCNT cannot be federally funded.

In 2014 FDA held a public meeting of the Cellular, Tissue, and Gene Therapy Advisory Committee (CGTAC) to discuss oocyte modification in assisted reproduction for the prevention of mitochondrial disease or treatment of infertility. Mitochondrial replacement techniques (MRT) are novel procedures where maternal nuclear DNA is transferred from her oocyte or zygote to a donor oocyte from which the nuclear DNA has been removed. In 2015 FDA requested that the Institute of Medicine (IOM) produce a consensus report regarding the ethical and social policy issues related to genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease 1. The report concluded that MRT in humans is ethically permissible as long as certain conditions and principles are met. One condition is that treatment should be limited to women who are at risk of transmitting severe mitochondrial disease and because female embryos would result in heritable genetic modification, MRT research should be restricted initially to male embryos.

The field of genetics is moving rapidly with new techniques that focus on DNA manipulation in vivo resulting in the alteration of genes to correct mutations, introduce new genetic information, and remove specific DNA sequences. Zinc-Finger Nucleases, TALENs and CRISPR/Cas9 are a few of the genome editing tools that are now available to the scientific research community. To address the societal issues surrounding genome editing, the International Summit on Human Gene Editing, hosted by the scientific academies of China, the United Kingdom and the U.S. was held in December 2015 in Washington DC. The summit concluded that somatic therapies based on genome editing should proceed under the existing FDA regulatory framework, but editing the human germline would be irresponsible to pursue at this time.

FDA has regulatory authority over genetically manipulated cells and/or their derivatives and requires submission of an Investigational New Drug application (IND) before a clinical study can proceed. FDA’s regulations on investigational new drugs, including those for the submission and review of an IND are described in Title 21 of the Code of Federal Regulations (CFR), Parts 50, 56, and 312. A Federal Register (FR) notice describing FDA’s authority over cell and gene therapy products (“Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products”) was published on October 14, 1993, (58 FR 53248) and a final rule establishing criteria for regulation of human cellular and tissue- based products (HCT/P) based on a tiered approach, including reproductive cells and tissues was published on January 19, 2001.

Here’s How The FDA Developed Rules For Therapeutic Cloning and Genome Modification was last modified: July 21st, 2020 by Staff